VCV000099390.52 - ClinVar

NM_000350.3(ABCA4):c.5603A>T (p.Asn1868Ile)

Germline

Classification

The aggregate germline classification for this variant, typically for a monogenic or Mendelian disorder as in the ACMG/AMP guidelines, or for response to a drug. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the aggregate classification.

(20)

Stars represent the aggregate review status, or the level of review supporting the aggregate germline classification for this VCV record. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the review status. The number of submissions which contribute to this review status is shown in parentheses.

Conflicting classifications of pathogenicity
Likely pathogenic(2); Established risk allele(2); Uncertain significance(5); Benign(3); Likely benign(5)

criteria provided, conflicting classifications

Somatic

No data submitted for somatic clinical impact

Somatic

No data submitted for oncogenicity

Variant Details

This variant is part of 5 Haplotypes

Identifiers

NM_000350.3(ABCA4):c.5603A>T (p.Asn1868Ile)

Variation ID: 99390 Accession: VCV000099390.52

Type and length

single nucleotide variant, 1 bp

Location

Cytogenetic: 1p22.1 1: 94010911 (GRCh38) [ NCBI UCSC ] 1: 94476467 (GRCh37) [ NCBI UCSC ]

Timeline in ClinVar

	First in ClinVar Help The date this variant first appeared in ClinVar with each type of classification.	Last submission Help The date of the most recent submission for each type of classification for this variant.	Last evaluated Help The most recent date that a submitter evaluated this variant for each type of classification.
Germline	Feb 20, 2014	Dec 28, 2024	Mar 5, 2024

HGVS

Nucleotide	Protein	Molecular consequence
NM_000350.3:c.5603A>T MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.	NP_000341.2:p.Asn1868Ile	missense
NM_001425324.1:c.5381A>T	NP_001412253.1:p.Asn1794Ile	missense
NC_000001.11:g.94010911T>A
NC_000001.10:g.94476467T>A
NG_009073.1:g.115239A>T
NG_009073.2:g.115237A>T
	P78363:p.Asn1868Ile

... more HGVS ... less HGVS

Protein change

N1868I, N1794I

Other names

p.N1868I:AAT>ATT

Canonical SPDI

NC_000001.11:94010910:T:A

Functional consequence Help The effect of the variant on RNA or protein function, based on experimental evidence from submitters.

Global minor allele frequency (GMAF) Help The global minor allele frequency calculated by the 1000 Genomes Project. The minor allele at this location is indicated in parentheses and may be different from the allele represented by this VCV record.

0.02077 (A)

Allele frequency Help The frequency of the allele represented by this VCV record.

1000 Genomes Project 0.02077

1000 Genomes Project 30x 0.02124

Trans-Omics for Precision Medicine (TOPMed) 0.03802

The Genome Aggregation Database (gnomAD) 0.04126

The Genome Aggregation Database (gnomAD), exomes 0.04255

Exome Aggregation Consortium (ExAC) 0.04456

NHLBI Exome Sequencing Project (ESP) Exome Variant Server 0.04775

Links

ClinGen: CA202869 UniProtKB: P78363#VAR_008470 dbSNP: rs1801466 VarSome

Genes

Gene	OMIM	ClinGen Gene Dosage Sensitivity Curation		Variation Viewer Help Links to Variation Viewer, a genome browser to view variation data from NCBI databases.	Related variants
Gene	OMIM	HI score Help The haploinsufficiency score for the gene, curated by ClinGen’s Dosage Sensitivity Curation task team.	TS score Help The triplosensitivity score for the gene, curated by ClinGen’s Dosage Sensitivity Curation task team.		Within gene Help The number of variants in ClinVar that are contained within this gene, with a link to view the list of variants.	All Help The number of variants in ClinVar for this gene, including smaller variants within the gene and larger CNVs that overlap or fully contain the gene.
ABCA4		-	-	GRCh38 GRCh37	3864	4234

Conditions - Germline

Condition Help The condition for this variant-condition (RCV) record in ClinVar.	Classification Help The aggregate germline classification for this variant-condition (RCV) record in ClinVar. The number of submissions that contribute to this aggregate classification is shown in parentheses. (# of submissions)	Review status Help The aggregate review status for this variant-condition (RCV) record in ClinVar. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the review status.	Last evaluated Help The most recent date that a submitter evaluated this variant for the condition.	Variation/condition record Help The RCV accession number, with most recent version number, for the variant-condition record, with a link to the RCV web page.
Macular degeneration	Likely benign (1)	criteria provided, single submitter	Jun 14, 2016	RCV000391356.13
not provided	Conflicting classifications of pathogenicity (4)	criteria provided, conflicting classifications	Dec 18, 2021	RCV000085744.43
Age related macular degeneration 2	Uncertain significance (1)	criteria provided, single submitter	Jun 27, 2019	RCV001197336.10
Cone-rod dystrophy 3	Uncertain significance (1)	criteria provided, single submitter	Jan 1, 2019	RCV001262623.9
Retinitis Pigmentosa, Recessive	Likely benign (1)	criteria provided, single submitter	Jun 14, 2016	RCV000348932.13
Stargardt disease	Likely pathogenic (1)	no assertion criteria provided	Jun 23, 2019	RCV001002812.9
not specified	Benign (1)	criteria provided, multiple submitters, no conflicts	May 20, 2014	RCV000178424.16
Cone-Rod Dystrophy, Recessive	Likely benign (1)	criteria provided, single submitter	Jun 14, 2016	RCV000293913.13
Stargardt Disease, Recessive	Likely benign (1)	criteria provided, single submitter	Jun 14, 2016	RCV000309306.13
Retinitis pigmentosa	Likely pathogenic (1)	criteria provided, single submitter	Apr 1, 2021	RCV001723669.11
Severe early-childhood-onset retinal dystrophy	Conflicting classifications of pathogenicity (4)	criteria provided, conflicting classifications	Jun 23, 2022	RCV000721173.16
ABCA4-related disorder	Conflicting classifications of pathogenicity (2)	criteria provided, conflicting classifications	Mar 5, 2024	RCV001097975.14
Retinal dystrophy	Uncertain significance (1)	criteria provided, single submitter	Jan 1, 2023	RCV004815126.1
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Submissions - Germline

Classification Help The submitted germline classification for each SCV record. (Last evaluated)	Review status Help Stars represent the review status, or the level of review supporting the submitted (SCV) record. This value is calculated by NCBI based on data from the submitter. Read our rules for calculating the review status. This column also includes a link to the submitter’s assertion criteria if provided, and the collection method. (Assertion criteria)	Condition Help The condition for the classification, provided by the submitter for this submitted (SCV) record. This column also includes the affected status and allele origin of individuals observed with this variant.	Submitter Help The submitting organization for this submitted (SCV) record. This column also includes the SCV accession and version number, the date this SCV first appeared in ClinVar, and the date that this SCV was last updated in ClinVar.	More information Help This column includes more information supporting the classification, including citations, the comment on classification, and detailed evidence provided as observations of the variant by the submitter.
Benign (May 20, 2014)	criteria provided, single submitter (EGL Classification Definitions 2015) Method: clinical testing	not specified Affected status: unknown Allele origin: germline	Eurofins Ntd Llc (ga) Accession: SCV000230500.5 First in ClinVar: Jun 28, 2015 Last updated: Oct 02, 2016	Other databases http://www.egl-eurofins.com/emvc… http://www.egl-eurofins.com/emvclass/emvclass.php?approved_symbol=ABCA4 Number of individuals with the variant: 1 Zygosity: Homozygote Sex: mixed
Likely pathogenic (Jan 30, 2021)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Severe early-childhood-onset retinal dystrophy Affected status: yes Allele origin: germline	Institute of Medical Molecular Genetics, University of Zurich Accession: SCV001548165.1 First in ClinVar: Mar 28, 2021 Last updated: Mar 28, 2021	Publications: PubMed (1) PubMed: 33546218 Method: long-range PCR
Likely pathogenic (Apr 01, 2021)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: curation	Retinitis pigmentosa (Autosomal recessive inheritance) Affected status: yes Allele origin: germline	Broad Center for Mendelian Genomics, Broad Institute of MIT and Harvard Accession: SCV001950192.1 First in ClinVar: Oct 02, 2021 Last updated: Oct 02, 2021	Publications: PubMed (10) PubMed: 34906470‚ 29971439‚ 28446513‚ 28118664‚ 11328725‚ 11017087‚ 29555955‚ 30480703‚ 24265693‚ 21330655 Comment: The p.Asn1868Ile variant in ABCA4 was identified in an individual with Retinitis pigmentosa, via a collaborative study between the Broad Institute's Center for Mendelian Genomics … (more) The p.Asn1868Ile variant in ABCA4 was identified in an individual with Retinitis pigmentosa, via a collaborative study between the Broad Institute's Center for Mendelian Genomics and the Pierce lab (https://oculargenomics.meei.harvard.edu/labs/pierce-lab/lab-members/). Through a review of available evidence we were able to apply the following criteria: PS3, PM3, PM3, BP2. Based on this evidence we have classified this variant as Likely Pathogenic. If you have any questions about the classification please reach out to the Pierce Lab. (less)
Benign (Dec 18, 2021)	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015)) Method: clinical testing	not provided Affected status: unknown Allele origin: germline	Labcorp Genetics (formerly Invitae), Labcorp Accession: SCV001731765.2 First in ClinVar: Jun 15, 2021 Last updated: May 16, 2022
Established risk allele (Mar 05, 2024)	criteria provided, single submitter (Schmidt et al. (Genet Med. 2023)) Method: clinical testing	ABCA4-related condition Affected status: unknown Allele origin: germline	PreventionGenetics, part of Exact Sciences Accession: SCV000303765.2 First in ClinVar: Oct 02, 2016 Last updated: Mar 10, 2024	Publications: PubMed (1) PubMed: 38054408 Comment: This variant is reported with a global allele frequency of 4.2% in gnomAD, with the highest population frequency being 6.6% in individuals of European (Non-Finnish) … (more) This variant is reported with a global allele frequency of 4.2% in gnomAD, with the highest population frequency being 6.6% in individuals of European (Non-Finnish) descent, including hundreds of homozygous individuals. Allele frequencies this high are most often associated with variants that are considered benign for Mendelian disease. However, statistical analyses have shown that this variant is significantly enriched in Stargardt patient populations compared to controls (Webster et al. 2001. PubMed ID: 11328725; Aguirre-Lamban et al. 2011. PubMed ID: 21330655). Large cohort studies of individuals with only one known pathogenic variant in ABCA4 found that this c.5603A>T (p.Asn1868Ile) variant could explain ~50% of those missing heritability cases (Zernant et al. 2017. PubMed ID: 28446513; Bauwens et al. 2019. PubMed ID: 30670881). Despite the enrichment in the patient population, the very high allele frequency has been used to estimate that the penetrance of this variant is less than 5% (Runhart et al. 2018. PubMed ID: 29971439). Additionally, it has been demonstrated that patients who harbor this variant have a more mild phenotype and an average age of onset in the 4th decade compared to the typical juvenile-onset associated with ABCA4 disease (Zernant et al. 2017. PubMed ID: 28446513; Bauwens et al. 2019. PubMed ID: 30670881). Functional studies have shown that this variant causes a small but significant decrease in the ATPase activity (Sun et al. 2000. PubMed ID: 11017087) and a decrease in substrate binding ability (Garces et al. 2021. PubMed ID: 33375396). This variant has often been found in cis with other ABCA4 variants such as c.2588G>C, c.5461-10T>C, and many others; forming a complex allele which can modify the penetrance and severity of disease (Zernant et al. 2017. PubMed ID: 28446513; Bauwens et al. 2019. PubMed ID: 30670881). Given all the evidence, we interpret c.5603A>T (p.Asn1868Ile) as a risk variant for mild and late-onset disease when in trans with a severe variant. (less)
Uncertain significance (Aug 01, 2018)	criteria provided, single submitter (CeGaT Center For Human Genetics Tuebingen Variant Classification Criteria Version 2) Method: clinical testing	not provided Affected status: yes Allele origin: germline	CeGaT Center for Human Genetics Tuebingen Accession: SCV000493309.32 First in ClinVar: May 29, 2016 Last updated: Dec 22, 2024	Number of individuals with the variant: 6
Likely benign (Jun 14, 2016)	criteria provided, single submitter (ICSL Variant Classification 20161018) Method: clinical testing	Macular Degeneration Affected status: unknown Allele origin: germline	Illumina Laboratory Services, Illumina Accession: SCV000359266.2 First in ClinVar: Dec 06, 2016 Last updated: Dec 06, 2016
Likely benign (Jun 14, 2016)	criteria provided, single submitter (ICSL Variant Classification 20161018) Method: clinical testing	Retinitis Pigmentosa, Recessive Affected status: unknown Allele origin: germline	Illumina Laboratory Services, Illumina Accession: SCV000359265.2 First in ClinVar: Dec 06, 2016 Last updated: Dec 06, 2016
Likely benign (Jun 14, 2016)	criteria provided, single submitter (ICSL Variant Classification 20161018) Method: clinical testing	Stargardt Disease, Recessive Affected status: unknown Allele origin: germline	Illumina Laboratory Services, Illumina Accession: SCV000359267.2 First in ClinVar: Dec 06, 2016 Last updated: Dec 06, 2016
Likely benign (Jun 14, 2016)	criteria provided, single submitter (ICSL Variant Classification 20161018) Method: clinical testing	Cone-Rod Dystrophy, Recessive Affected status: unknown Allele origin: germline	Illumina Laboratory Services, Illumina Accession: SCV000359264.2 First in ClinVar: Dec 06, 2016 Last updated: Dec 06, 2016
Uncertain significance (May 28, 2019)	criteria provided, single submitter (Mendelics Assertion Criteria 2017) Method: clinical testing	Severe early-childhood-onset retinal dystrophy Affected status: unknown Allele origin: unknown	Mendelics Accession: SCV001135331.1 First in ClinVar: Jan 09, 2020 Last updated: Jan 09, 2020
Likely benign (Apr 27, 2017)	criteria provided, single submitter (ICSL Variant Classification Criteria 13 December 2019) Method: clinical testing	ABCA4-Related Disorders Affected status: unknown Allele origin: germline	Illumina Laboratory Services, Illumina Accession: SCV001254309.1 First in ClinVar: May 31, 2020 Last updated: May 31, 2020	Comment: This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, … (more) This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). No publications were found based on this search. Allele frequency data from public databases allowed determination this variant is unlikely to cause disease. Therefore, this variant is classified as likely benign. (less)
Uncertain significance (Jan 01, 2019)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Cone-rod dystrophy 3 Affected status: yes Allele origin: unknown	Institute of Human Genetics, University of Leipzig Medical Center Accession: SCV001440560.1 First in ClinVar: Oct 31, 2020 Last updated: Oct 31, 2020	Comment: This variant was identified as compound heterozygous.
Uncertain significance (Jun 27, 2019)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Age related macular degeneration 2 Affected status: yes Allele origin: unknown	Centre for Mendelian Genomics, University Medical Centre Ljubljana Accession: SCV001368030.2 First in ClinVar: Jul 04, 2020 Last updated: Jul 04, 2020	Comment: This variant was classified as: Uncertain significance. The available evidence favors the pathogenic nature of this variant, however the currently available data is insufficient to … (more) This variant was classified as: Uncertain significance. The available evidence favors the pathogenic nature of this variant, however the currently available data is insufficient to conclusively support its pathogenic nature. Thus this variant is classified as Uncertain significance - favor pathogenic. The following ACMG criteria were applied in classifying this variant: PP2,PP3,BS1. (less)
Established risk allele (Jun 23, 2022)	criteria provided, single submitter (ClinGen Low Penetrance/Risk Allele Working Group Recommended Terminology – Version 1.0) Method: clinical testing	Severe early-childhood-onset retinal dystrophy Affected status: yes Allele origin: unknown	Institute of Human Genetics, University of Leipzig Medical Center Accession: SCV002549835.1 First in ClinVar: Jul 23, 2022 Last updated: Jul 23, 2022	Comment: This variant was identified as compound heterozygous with NM_000350.3:c.67-2A>G
Benign (Jan 28, 2019)	criteria provided, single submitter (GeneDx Variant Classification Process June 2021) Method: clinical testing	Not Provided Affected status: yes Allele origin: germline	GeneDx Accession: SCV000166748.12 First in ClinVar: Jun 23, 2014 Last updated: Mar 04, 2023	Comment: The variant in the ABCA4 gene that is indicated below was identified in this patient and is not currently known to cause an ABCA4-related disorder. … (more) The variant in the ABCA4 gene that is indicated below was identified in this patient and is not currently known to cause an ABCA4-related disorder. The variant is observed in 8,580/129,074 (6.65%) alleles from individuals of non-Finnish European background and in 11,928/282,712 (4.22%) global alleles, including 364 homozygous individuals, in large population cohorts (Lek et al., 2016). However, some publications theorize N1868I may cause hypomorphic retinal dystrophy only when in trans with a pathogenic ABCA4 variant (Zernant et al., 2017; Runhart et al., 2018). Individuals who had the N1868I variant in trans with another ABCA4 pathogenic variant were reported to have late-onset Stargardt disease (Zernant et al., 2017; Runhart et al,. 2018).; This variant is associated with the following publications: (PMID: 26780318, 21330655, 32845050, 28118664, 11328725, 28446513, 27775217, 24265693, 11017087, 29555955, 29971439, 23443024, 30204727, 30480703, 30480704, 29925512, 30670881, 30643219, 31618761, 31456290, 32467599, 32037395) (less)
Uncertain significance (Jan 01, 2023)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Retinal dystrophy Affected status: yes Allele origin: germline	Institute of Human Genetics, Univ. Regensburg, Univ. Regensburg Accession: SCV005069856.1 First in ClinVar: Dec 28, 2024 Last updated: Dec 28, 2024	Publications: PubMed (44) PubMed: 11328725‚ 11017087‚ 21330655‚ 24265693‚ 26780318‚ 27775217‚ 28446513‚ 30480703‚ 29555955‚ 30204727‚ 30480704‚ 29971439‚ 30670881‚ 29925512‚ 31618761‚ 30643219‚ 32845050‚ 32619608‚ 33375396‚ 32467599‚ 31964843‚ 31429209‚ 32307445‚ 32815999‚ 31456290‚ 32531858‚ 32037395‚ 33706644‚ 34795310‚ 34946930‚ 34198153‚ 34240658‚ 33851411‚ 36338671‚ 35243166‚ 35119454‚ 35260635‚ 35656873‚ 36460718‚ 35836572‚ 35076026‚ 35657619‚ 36672815‚ 36819107
other (Sep 10, 2018)	no assertion criteria provided Method: clinical testing	Severe early-childhood-onset retinal dystrophy Affected status: yes Allele origin: germline	Molecular Vision Laboratory Accession: SCV000852088.1 First in ClinVar: Nov 17, 2018 Last updated: Nov 17, 2018	Publications: PubMed (3) PubMed: 28118664‚ 29971439‚ 28446513 Comment: Asn1868Ile has been found to be associated with autosomal recessive Stargardt disease (STGD1). Its presence explained >40% of monoallelic ABCA4 carriers in two separate STGD1 … (more) Asn1868Ile has been found to be associated with autosomal recessive Stargardt disease (STGD1). Its presence explained >40% of monoallelic ABCA4 carriers in two separate STGD1 cohorts. Penetrance was estimated to be less than 5% based on expected incidence of Asn1868Ile combinations with severe ABCA4 mutations and estimated prevalence of cases due to these combinations in a STGD1 cohort. (less)
Likely pathogenic (Jun 23, 2019)	no assertion criteria provided Method: research	Stargardt disease Affected status: yes Allele origin: inherited	Sharon lab, Hadassah-Hebrew University Medical Center Accession: SCV001160826.1 First in ClinVar: Feb 16, 2020 Last updated: Feb 16, 2020
not provided (-)	no classification provided Method: not provided	not provided Affected status: not provided Allele origin: unknown	Retina International Accession: SCV000117885.1 First in ClinVar: Feb 20, 2014 Last updated: Feb 20, 2014 Comment: http://phencode.bx.psu.edu/cgi-bin/phencode/phencode?build=hg19&id=RISN_ABCR:c.5603A>T
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Comment:

The p.Asn1868Ile variant in ABCA4 was identified in an individual with Retinitis pigmentosa, via a collaborative study between the Broad Institute's Center for Mendelian Genomics and the Pierce lab (https://oculargenomics.meei.harvard.edu/labs/pierce-lab/lab-members/). Through a review of available evidence we were able to apply the following criteria: PS3, PM3, PM3, BP2. Based on this evidence we have classified this variant as Likely Pathogenic. If you have any questions about the classification please reach out to the Pierce Lab.

Comment:

This variant is reported with a global allele frequency of 4.2% in gnomAD, with the highest population frequency being 6.6% in individuals of European (Non-Finnish) descent, including hundreds of homozygous individuals. Allele frequencies this high are most often associated with variants that are considered benign for Mendelian disease. However, statistical analyses have shown that this variant is significantly enriched in Stargardt patient populations compared to controls (Webster et al. 2001. PubMed ID: 11328725; Aguirre-Lamban et al. 2011. PubMed ID: 21330655). Large cohort studies of individuals with only one known pathogenic variant in ABCA4 found that this c.5603A>T (p.Asn1868Ile) variant could explain ~50% of those missing heritability cases (Zernant et al. 2017. PubMed ID: 28446513; Bauwens et al. 2019. PubMed ID: 30670881). Despite the enrichment in the patient population, the very high allele frequency has been used to estimate that the penetrance of this variant is less than 5% (Runhart et al. 2018. PubMed ID: 29971439). Additionally, it has been demonstrated that patients who harbor this variant have a more mild phenotype and an average age of onset in the 4th decade compared to the typical juvenile-onset associated with ABCA4 disease (Zernant et al. 2017. PubMed ID: 28446513; Bauwens et al. 2019. PubMed ID: 30670881). Functional studies have shown that this variant causes a small but significant decrease in the ATPase activity (Sun et al. 2000. PubMed ID: 11017087) and a decrease in substrate binding ability (Garces et al. 2021. PubMed ID: 33375396). This variant has often been found in cis with other ABCA4 variants such as c.2588G>C, c.5461-10T>C, and many others; forming a complex allele which can modify the penetrance and severity of disease (Zernant et al. 2017. PubMed ID: 28446513; Bauwens et al. 2019. PubMed ID: 30670881). Given all the evidence, we interpret c.5603A>T (p.Asn1868Ile) as a risk variant for mild and late-onset disease when in trans with a severe variant.

Comment:

This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). No publications were found based on this search. Allele frequency data from public databases allowed determination this variant is unlikely to cause disease. Therefore, this variant is classified as likely benign.

Comment:

This variant was classified as: Uncertain significance. The available evidence favors the pathogenic nature of this variant, however the currently available data is insufficient to conclusively support its pathogenic nature. Thus this variant is classified as Uncertain significance - favor pathogenic. The following ACMG criteria were applied in classifying this variant: PP2,PP3,BS1.

Comment:

The variant in the ABCA4 gene that is indicated below was identified in this patient and is not currently known to cause an ABCA4-related disorder. The variant is observed in 8,580/129,074 (6.65%) alleles from individuals of non-Finnish European background and in 11,928/282,712 (4.22%) global alleles, including 364 homozygous individuals, in large population cohorts (Lek et al., 2016). However, some publications theorize N1868I may cause hypomorphic retinal dystrophy only when in trans with a pathogenic ABCA4 variant (Zernant et al., 2017; Runhart et al., 2018). Individuals who had the N1868I variant in trans with another ABCA4 pathogenic variant were reported to have late-onset Stargardt disease (Zernant et al., 2017; Runhart et al,. 2018).; This variant is associated with the following publications: (PMID: 26780318, 21330655, 32845050, 28118664, 11328725, 28446513, 27775217, 24265693, 11017087, 29555955, 29971439, 23443024, 30204727, 30480703, 30480704, 29925512, 30670881, 30643219, 31618761, 31456290, 32467599, 32037395)

Comment:

Asn1868Ile has been found to be associated with autosomal recessive Stargardt disease (STGD1). Its presence explained >40% of monoallelic ABCA4 carriers in two separate STGD1 cohorts. Penetrance was estimated to be less than 5% based on expected incidence of Asn1868Ile combinations with severe ABCA4 mutations and estimated prevalence of cases due to these combinations in a STGD1 cohort.

Germline Functional Evidence

There is no functional evidence in ClinVar for this variation. If you have generated functional data for this variation, please consider submitting that data to ClinVar.

Comment:

Citations for germline classification of this variant

Title	Author	Journal	Year	Link
Recommendations for risk allele evidence curation, classification, and reporting from the ClinGen Low Penetrance/Risk Allele Working Group.	Schmidt RJ	Genetics in medicine : official journal of the American College of Medical Genetics	2024	PMID: 38054408
Cost-effective sequence analysis of 113 genes in 1,192 probands with retinitis pigmentosa and Leber congenital amaurosis.	Panneman DM	Frontiers in cell and developmental biology	2023	PMID: 36819107
Genetic Diagnosis for 64 Patients with Inherited Retinal Disease.	Lynn J	Genes	2022	PMID: 36672815
Genetic epidemiology of inherited retinal diseases in a large patient cohort followed at a single center in Italy.	Karali M	Scientific reports	2022	PMID: 36460718
A five-year follow-up of ABCA4 carriers showing deterioration of retinal function and increased structural changes.	Kjellström U	Molecular vision	2022	PMID: 36338671
Genetics of Inherited Retinal Diseases in Understudied Ethnic Groups in Italian Hospitals.	Maltese PE	Frontiers in genetics	2022	PMID: 35836572
Phenotype-Based Genetic Analysis Reveals Missing Heritability of ABCA4-Related Retinopathy: Deep Intronic Variants and Copy Number Variations.	Tian L	Investigative ophthalmology & visual science	2022	PMID: 35657619
Panel-based next-generation sequencing identifies novel mutations in Bulgarian patients with inherited retinal dystrophies.	Kamenarova K	Molecular genetics & genomic medicine	2022	PMID: 35656873
Genetic characteristics of 234 Italian patients with macular and cone/cone-rod dystrophy.	Falsini B	Scientific reports	2022	PMID: 35260635
Late-onset Stargardt disease.	Alsberge JB	American journal of ophthalmology case reports	2022	PMID: 35243166
Impact of Next Generation Sequencing in Unraveling the Genetics of 1036 Spanish Families With Inherited Macular Dystrophies.	Del Pozo-Valero M	Investigative ophthalmology & visual science	2022	PMID: 35119454
Photoreceptor degeneration in ABCA4-associated retinopathy and its genetic correlates.	Pfau M	JCI insight	2022	PMID: 35076026
The importance of automation in genetic diagnosis: Lessons from analyzing an inherited retinal degeneration cohort with the Mendelian Analysis Toolkit (MATK).	Zampaglione E	Genetics in medicine : official journal of the American College of Medical Genetics	2022	PMID: 34906470
Genotype-Specific Lesion Growth Rates in Stargardt Disease.	Heath Jeffery RC	Genes	2021	PMID: 34946930
Whole genome sequencing and in vitro splice assays reveal genetic causes for inherited retinal diseases.	Fadaie Z	NPJ genomic medicine	2021	PMID: 34795310
Clinical and molecular findings in patients with pattern dystrophy.	Sodi A	Ophthalmic genetics	2021	PMID: 34240658
Generation of two induced pluripotent stem cell lines from a patient with Stargardt disease caused by compound heterozygous mutations in the ABCA4 gene.	Huang D	Stem cell research	2021	PMID: 34198153
Molecular genetics of inherited retinal degenerations in Icelandic patients.	Thorsteinsson DA	Clinical genetics	2021	PMID: 33851411
Peripheral pigmented lesions in ABCA4-associated retinopathy.	Al-Ani HH	Ophthalmic genetics	2021	PMID: 33706644
Long-Range PCR-Based NGS Applications to Diagnose Mendelian Retinal Diseases.	Maggi J	International journal of molecular sciences	2021	PMID: 33546218
Functional Characterization of ABCA4 Missense Variants Linked to Stargardt Macular Degeneration.	Garces FA	International journal of molecular sciences	2020	PMID: 33375396
Functional analysis and classification of homozygous and hypomorphic ABCA4 variants associated with Stargardt macular degeneration.	Curtis SB	Human mutation	2020	PMID: 32845050
Association of Sex With Frequent and Mild ABCA4 Alleles in Stargardt Disease.	Runhart EH	JAMA ophthalmology	2020	PMID: 32815999
Genotype-Phenotype Correlations in a Spanish Cohort of 506 Families With Biallelic ABCA4 Pathogenic Variants.	Del Pozo-Valero M	American journal of ophthalmology	2020	PMID: 32619608
Genetic architecture of inherited retinal degeneration in Germany: A large cohort study from a single diagnostic center over a 9-year period.	Weisschuh N	Human mutation	2020	PMID: 32531858
The genetic architecture of Stargardt macular dystrophy (STGD1): a longitudinal 40-year study in a genetic isolate.	Green JS	European journal of human genetics : EJHG	2020	PMID: 32467599
Resolving the dark matter of ABCA4 for 1054 Stargardt disease probands through integrated genomics and transcriptomics.	Khan M	Genetics in medicine : official journal of the American College of Medical Genetics	2020	PMID: 32307445
Copy-number variation contributes 9% of pathogenicity in the inherited retinal degenerations.	Zampaglione E	Genetics in medicine : official journal of the American College of Medical Genetics	2020	PMID: 32037395
Worldwide carrier frequency and genetic prevalence of autosomal recessive inherited retinal diseases.	Hanany M	Proceedings of the National Academy of Sciences of the United States of America	2020	PMID: 31964843
A nationwide genetic analysis of inherited retinal diseases in Israel as assessed by the Israeli inherited retinal disease consortium (IIRDC).	Sharon D	Human mutation	2020	PMID: 31456290
Inherited retinal disease in Norway - a characterization of current clinical and genetic knowledge.	Holtan JP	Acta ophthalmologica	2020	PMID: 31429209
Late-Onset Stargardt Disease Due to Mild, Deep-Intronic ABCA4 Alleles.	Runhart EH	Investigative ophthalmology & visual science	2019	PMID: 31618761
ABCA4-associated disease as a model for missing heritability in autosomal recessive disorders: novel noncoding splice, cis-regulatory, structural, and recurrent hypomorphic variants.	Bauwens M	Genetics in medicine : official journal of the American College of Medical Genetics	2019	PMID: 30670881
Deep-intronic ABCA4 variants explain missing heritability in Stargardt disease and allow correction of splice defects by antisense oligonucleotides.	Sangermano R	Genetics in medicine : official journal of the American College of Medical Genetics	2019	PMID: 30643219
CLINICAL CHARACTERIZATION OF STARGARDT DISEASE PATIENTS WITH THE p.N1868I ABCA4 MUTATION.	Collison FT	Retina (Philadelphia, Pa.)	2019	PMID: 30204727
Detailed genetic characteristics of an international large cohort of patients with Stargardt disease: ProgStar study report 8.	Fujinami K	The British journal of ophthalmology	2019	PMID: 29925512
Author Response: Penetrance of the ABCA4 p.Asn1868Ile Allele in Stargardt Disease.	Cremers FPM	Investigative ophthalmology & visual science	2018	PMID: 30480704
Penetrance of the ABCA4 p.Asn1868Ile Allele in Stargardt Disease.	Allikmets R	Investigative ophthalmology & visual science	2018	PMID: 30480703
The Common ABCA4 Variant p.Asn1868Ile Shows Nonpenetrance and Variable Expression of Stargardt Disease When Present in trans With Severe Variants.	Runhart EH	Investigative ophthalmology & visual science	2018	PMID: 29971439
Clinical and genetic characteristics of 251 consecutive patients with macular and cone/cone-rod dystrophy.	Birtel J	Scientific reports	2018	PMID: 29555955
Frequent hypomorphic alleles account for a significant fraction of ABCA4 disease and distinguish it from age-related macular degeneration.	Zernant J	Journal of medical genetics	2017	PMID: 28446513
Mutation Spectrum of the ABCA4 Gene in 335 Stargardt Disease Patients From a Multicenter German Cohort-Impact of Selected Deep Intronic Variants and Common SNPs.	Schulz HL	Investigative ophthalmology & visual science	2017	PMID: 28118664
The intronic ABCA4 c.5461-10T>C variant, frequently seen in patients with Stargardt disease, causes splice defects and reduced ABCA4 protein level.	Aukrust I	Acta ophthalmologica	2017	PMID: 27775217
Screening of ABCA4 Gene in a Chinese Cohort With Stargardt Disease or Cone-Rod Dystrophy With a Report on 85 Novel Mutations.	Jiang F	Investigative ophthalmology & visual science	2016	PMID: 26780318
Increasing the yield in targeted next-generation sequencing by implicating CNV analysis, non-coding exons and the overall variant load: the example of retinal dystrophies.	Eisenberger T	PloS one	2013	PMID: 24265693
Further associations between mutations and polymorphisms in the ABCA4 gene: clinical implication of allelic variants and their role as protector/risk factors.	Aguirre-Lamban J	Investigative ophthalmology & visual science	2011	PMID: 21330655
An analysis of allelic variation in the ABCA4 gene.	Webster AR	Investigative ophthalmology & visual science	2001	PMID: 11328725
Biochemical defects in ABCR protein variants associated with human retinopathies.	Sun H	Nature genetics	2000	PMID: 11017087
http://www.egl-eurofins.com/emvclass/emvclass.php?approved_symbol=ABCA4	-	-	-	-
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Text-mined citations for rs1801466 ...

These citations are identified by LitVar using the rs number, so they may include citations for more than one variant at this location. Please review the LitVar results carefully for your variant of interest.

Record last updated Feb 01, 2025

ClinVar Genomic variation as it relates to human health

NM_000350.3(ABCA4):c.5603A>T (p.Asn1868Ile)

Variant Details

Genes

Conditions - Germline

Submissions - Germline

Germline Functional Evidence

Citations for germline classification of this variant

Text-mined citations for rs1801466 ...