VCV000011742.23 - ClinVar

NM_000489.6(ATRX):c.109C>T (p.Arg37Ter)

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.

(13)

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.

Pathogenic/Likely pathogenic

criteria provided, multiple submitters, no conflicts

Somatic

No data submitted for somatic clinical impact

Somatic

No data submitted for oncogenicity

Variant Details

Identifiers

NM_000489.6(ATRX):c.109C>T (p.Arg37Ter)

Variation ID: 11742 Accession: VCV000011742.23

Type and length

single nucleotide variant, 1 bp

Location

Cytogenetic: Xq21.1 X: 77717155 (GRCh38) [ NCBI UCSC ] X: 76972632 (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	Apr 4, 2013	Nov 30, 2024	Jun 23, 2023

HGVS

Nucleotide	Protein	Molecular consequence
NM_000489.6:c.109C>T MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.	NP_000480.3:p.Arg37Ter	nonsense
NM_000489.5:c.109C>T
NM_138270.5:c.109C>T	NP_612114.2:p.Arg37Ter	nonsense
NC_000023.11:g.77717155G>A
NC_000023.10:g.76972632G>A
NG_008838.3:g.74115C>T
LRG_1153:g.74115C>T

... more HGVS ... less HGVS

Protein change

R37*

Other names

Canonical SPDI

NC_000023.11:77717154:G: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.

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

Links

ClinGen: CA121653 OMIM: 300032.0022 dbSNP: rs122445108 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.
ATRX		Sufficient evidence for dosage pathogenicity	No evidence available	GRCh38 GRCh37	2334	2498

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.
Intellectual disability-hypotonic facies syndrome, X-linked	Pathogenic (1)	no assertion criteria provided	Dec 1, 2004	RCV000012508.32
Alpha thalassemia-X-linked intellectual disability syndrome	Pathogenic (4)	criteria provided, multiple submitters, no conflicts	Jun 23, 2023	RCV000148028.19
Intellectual disability	Pathogenic/Likely pathogenic (2)	criteria provided, multiple submitters, no conflicts	Feb 13, 2019	RCV000224314.11
Intellectual disability-hypotonic facies syndrome, X-linked, 1	Pathogenic (3)	criteria provided, multiple submitters, no conflicts	Oct 2, 2021	RCV000680146.13
Inborn genetic diseases	Pathogenic (1)	criteria provided, single submitter	Dec 27, 2019	RCV002444427.9
not provided	Pathogenic (1)	criteria provided, single submitter	Sep 12, 2022	RCV003151722.8
Acquired hemoglobin H disease Alpha thalassemia-X-linked intellectual disability syndrome Intellectual disability-hypotonic facies syndrome, X-linked, 1	Pathogenic (1)	criteria provided, single submitter	-	RCV004795394.1

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.
Pathogenic (Jul 25, 2014)	criteria provided, single submitter (submitter's publication) Method: clinical testing	Intellectual disability Affected status: yes Allele origin: maternal	Diagnostic Laboratory, Strasbourg University Hospital Accession: SCV000281747.1 First in ClinVar: Jun 09, 2016 Last updated: Jun 09, 2016	Publications: PubMed (1) PubMed: 25167861 Number of individuals with the variant: 1 Zygosity: Hemizygote Sex: male
Likely pathogenic (Feb 13, 2019)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: research	Intellectual disability Affected status: yes Allele origin: unknown	Raymond Lab, University of Cambridge Accession: SCV000897756.1 First in ClinVar: Sep 16, 2019 Last updated: Sep 16, 2019	Number of individuals with the variant: 2 Family history: yes
Pathogenic (Jan 01, 2014)	criteria provided, single submitter (ACMG Guidelines, 2007) Method: clinical testing	Alpha thalassemia-X-linked intellectual disability syndrome Affected status: yes Allele origin: de novo	Equipe Genetique des Anomalies du Developpement, Université de Bourgogne Accession: SCV000965785.1 First in ClinVar: Aug 26, 2019 Last updated: Aug 26, 2019
Pathogenic (Oct 02, 2021)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Intellectual disability-hypotonic facies syndrome, X-linked, 1 Affected status: yes Allele origin: germline	3billion Accession: SCV002012304.1 First in ClinVar: Nov 13, 2021 Last updated: Nov 13, 2021	Comment: Stop-gained (nonsense): predicted to result in a loss or disruption of normal protein function through nonsense-mediated decay (NMD) or protein truncation. Multiple pathogenic variants are … (more) Stop-gained (nonsense): predicted to result in a loss or disruption of normal protein function through nonsense-mediated decay (NMD) or protein truncation. Multiple pathogenic variants are reported downstream of the variant (PVS1_VS). It is not observed in the gnomAD v2.1.1 dataset (PM2). The variant was observed as assumed (i.e. paternity and maternity not confirmed) de novoo (3billion dataset, PM6). The variant has been reported at least twice as pathogenic/likely pathogenic with clinical assertions and evidence for the classification (ClinVar ID: VCV000011742.7). Therefore, this variant is classified as pathogenic according to the recommendation of ACMG/AMP guideline. (less) Clinical Features: Delayed gross motor development (present) , Premature birth (present) , Abnormal lip morphology (present) , Delayed speech and language development (present) , Hypertelorism (present) , … (more) Delayed gross motor development (present) , Premature birth (present) , Abnormal lip morphology (present) , Delayed speech and language development (present) , Hypertelorism (present) , Specific learning disability (present) , Nephrolithiasis (present) , Attention deficit hyperactivity disorder (present) , Depressed nasal bridge (present) , Autistic behavior (present) , Proximal tubulopathy (present) , Fetal growth restriction (present) , Intellectual disability (present) (less) Zygosity: Hemizygote
Pathogenic (Jun 23, 2021)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Intellectual disability-hypotonic facies syndrome, X-linked, 1 Affected status: yes Allele origin: germline	Laboratorio de Genetica e Diagnostico Molecular, Hospital Israelita Albert Einstein Accession: SCV002512243.1 First in ClinVar: May 21, 2022 Last updated: May 21, 2022	Comment: ACMG classification criteria: PVS1 very strong, PS4 strong, PM2 moderate, PP1 very strong Geographic origin: Brazil
Pathogenic (Sep 01, 2017)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Intellectual disability-hypotonic facies syndrome, X-linked, 1 (X-linked inheritance) Affected status: yes Allele origin: maternal	Baylor Genetics Accession: SCV000807591.2 First in ClinVar: Sep 17, 2018 Last updated: Dec 11, 2022	Publications: PubMed (2) PubMed: 25326635‚ 10632111 Comment: This mutation has been previously reported as disease-causing and was found once in our laboratory in an 8-year-old male with intellectual disability, hypotonia, dysmorphic features, … (more) This mutation has been previously reported as disease-causing and was found once in our laboratory in an 8-year-old male with intellectual disability, hypotonia, dysmorphic features, GERD, febrile seizure, short stature, mirocephaly. (less)
Pathogenic (-)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Alpha thalassemia-X-linked intellectual disability syndrome Acquired hemoglobin H disease Intellectual disability-hypotonic facies syndrome, X-linked, 1 Explanation for multiple conditions: Uncertain. The variant was classified for several related diseases, possibly a spectrum of disease; the variant may be associated with one or more the diseases. Affected status: yes Allele origin: germline	Juno Genomics, Hangzhou Juno Genomics, Inc Accession: SCV005418309.1 First in ClinVar: Nov 30, 2024 Last updated: Nov 30, 2024	Comment: PVS1+PM2_Supporting+PS4_Moderate+PP1_Strong+PM6_Supporting
Pathogenic (Sep 12, 2022)	criteria provided, single submitter (GeneDx Variant Classification Process June 2021) Method: clinical testing	Not Provided Affected status: yes Allele origin: germline	GeneDx Accession: SCV003840738.1 First in ClinVar: Mar 18, 2023 Last updated: Mar 18, 2023	Comment: Segregates with X-linked intellectual disability, short stature, microcephaly, and dysmorphic features in multiple families; the heterozygous unaffected females showed skewed X-inactivation (Abidi et al., 2005; … (more) Segregates with X-linked intellectual disability, short stature, microcephaly, and dysmorphic features in multiple families; the heterozygous unaffected females showed skewed X-inactivation (Abidi et al., 2005; Basehore et al., 2015); Functional studies suggest that the variant may cause reduced protein expression compared to WT, however additional studies are needed to validate the impact of this variant on splicing (Howard et al., 2004); Nonsense variant predicted to result in protein truncation or nonsense mediated decay in a gene for which loss of function is a known mechanism of disease; Not observed at significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 25525159, 32170002, 3239563, 25606380, 18409179, 25167861, 25326635, 20301622, 28293299, 33173999, 25679214, 26147798, 31685013, 29491882, 26997013, 20865721, 32277047, 26350204, 30231518, 36031702, 12953102, 28152038, 31452935, 24805811, 10632111, 15508018, 32901917, 15591283) (less)
Pathogenic (Jun 23, 2023)	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015)) Method: clinical testing	Alpha thalassemia-X-linked intellectual disability syndrome Affected status: unknown Allele origin: germline	Labcorp Genetics (formerly Invitae), Labcorp Accession: SCV001582830.4 First in ClinVar: May 10, 2021 Last updated: Feb 14, 2024	Publications: PubMed (6) PubMed: 15508018‚ 15591283‚ 10632111‚ 24805811‚ 18409179‚ 23681356 Comment: Studies have shown that this premature translational stop signal does not significantly alter or has an unclear effect on ATRX gene expression (PMID: 15508018, 15591283). … (more) Studies have shown that this premature translational stop signal does not significantly alter or has an unclear effect on ATRX gene expression (PMID: 15508018, 15591283). For these reasons, this variant has been classified as Pathogenic. ClinVar contains an entry for this variant (Variation ID: 11742). This premature translational stop signal has been observed in individuals with clinical features of alpha-thalassemia X-linked intellectual disability syndrome (PMID: 10632111, 15508018, 24805811). It has also been observed to segregate with disease in related individuals. This variant is not present in population databases (gnomAD no frequency). This sequence change creates a premature translational stop signal (p.Arg37*) in the ATRX gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in ATRX are known to be pathogenic (PMID: 15591283, 18409179, 23681356). (less)
Pathogenic (Dec 27, 2019)	criteria provided, single submitter (Ambry Variant Classification Scheme 2023) Method: clinical testing	Inborn genetic diseases Affected status: unknown Allele origin: germline	Ambry Genetics Accession: SCV002733914.2 First in ClinVar: Nov 29, 2022 Last updated: May 01, 2024	Publications: PubMed (4) PubMed: 10632111‚ 15508018‚ 15591283‚ 24805811 Comment: The p.R37* pathogenic mutation (also known as c.109C>T), located in coding exon 2 of the ATRX gene, results from a C to T substitution at … (more) The p.R37* pathogenic mutation (also known as c.109C>T), located in coding exon 2 of the ATRX gene, results from a C to T substitution at nucleotide position 109. This changes the amino acid from an arginine to a stop codon within coding exon 2. This alteration has been shown to segregate with disease in several large families with variable intellectual disability (mild to profound), speech impairment, facial anomalies including +/- hypertelorism, short philtrum, open mouth, full lower lip, and microcephaly, growth deficiency, hypotonia, +/- seizures, +/- urogenital anomalies, and decreased Hgb H inclusions compared to most ATRX probands (Basehore MJ et al. Clin. Genet., 2015 May;87:461-6, Guerrini, R et al. Ann. Neurol. 2000;47(1):117-21, Moncini, S et al. Meta Gene 2013;1:102-108). This mutation is often observed to result in a less severe phenotype than is typically observed in patients with nonsense mutations in the ATRX gene, (Abidi, FE et al. Eur. J. Hum. Genet. 2005;13(2):176-83, Howard, MT et al. Med. Genet. 2004;41(12):951-6). Unaffected female carriers for this mutation have been observed to have highly skewed X-inactivation patterns of >90:10 (Abidi, FE et al. Eur. J. Hum. Genet. 2005;13(2):176-83, Basehore MJ et al. Clin. Genet., 2015 May;87:461-6). In addition to the clinical data presented in the literature, this alteration is expected to result in loss of function by premature protein truncation or nonsense-mediated mRNA decay. As such, this alteration is interpreted as a disease-causing mutation. (less)
Pathogenic (May 25, 2020)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Alpha thalassemia-X-linked intellectual disability syndrome (X-linked recessive inheritance) Affected status: yes Allele origin: germline	Victorian Clinical Genetics Services, Murdoch Childrens Research Institute Additional submitter: Shariant Australia, Australian Genomics Accession: SCV002769265.2 First in ClinVar: Dec 24, 2022 Last updated: Nov 24, 2024	Publications: PubMed (2) PubMed: 24805811‚ 26350204 Comment: Based on the classification scheme VCGS_Germline_v1.1.1, this variant is classified as Pathogenic. Following criteria are met: 0102 - Loss-of-function is a known mechanism of disease … (more) Based on the classification scheme VCGS_Germline_v1.1.1, this variant is classified as Pathogenic. Following criteria are met: 0102 - Loss-of-function is a known mechanism of disease for this gene. (N) 0109 - This gene is known to be associated with both X-linked dominant and recessive disease (OMIM). (N) 0201 - Variant is predicted to cause nonsense-mediated decay (NMD) and loss of protein (exon 2 of 35). (P) 0253 - Variant is hemizygous. (N) 0301 - Variant is absent from gnomAD. (P) 0701 - Comparable variants have very strong previous evidence for pathogenicity. Many other NMD-predicted variants have previously been reported as pathogenic (ClinVar). (P) 0801 - Strong previous evidence of pathogenicity in unrelated individuals. The variant has been previously reported in more than 20 male patients with intellectual disability (ClinVar, PMID: 26350204, PMID: 24805811). (P) 0901 - Strong evidence for segregation with disease. The variant has been shown to segregate with disease in affected males in at least 5 families, with unaffected female carriers (PMID: 24805811). (P) 1102 - Strong phenotype match. (P) 1205 - Variant is maternally inherited. (N) Legend: (P) - Pathogenic, (N) - Neutral, (B) - Benign (less)
Pathogenic (Dec 01, 2004)	no assertion criteria provided Method: literature only	INTELLECTUAL DISABILITY-HYPOTONIC FACIES SYNDROME, X-LINKED Affected status: not provided Allele origin: germline	OMIM Accession: SCV000032742.3 First in ClinVar: Apr 04, 2013 Last updated: Jun 09, 2024	Publications: PubMed (4) PubMed: 10632111‚ 15591283‚ 10398237‚ 3239563 Comment on evidence: In 4 male cousins with the X-linked intellectual disability-hypotonic facies syndrome (MRXHF1; 309580), Guerrini et al. (2000) identified a 109C-T transition in exon 2 of … (more) In 4 male cousins with the X-linked intellectual disability-hypotonic facies syndrome (MRXHF1; 309580), Guerrini et al. (2000) identified a 109C-T transition in exon 2 of the ATRX gene, resulting in an arg37-to-ter (R37X) substitution. Two patients had moderate to profound mental retardation and the typical facial features of the syndrome, whereas the other 2 patients presented with mild mental retardation and epilepsy, but without the characteristic facial dysmorphism. Howard et al. (2004) found that human embryonic kidney cells carrying the R37X mutation expressed approximately 20% of a slightly shortened ATRX protein compared to controls. Analysis of the 5-prime end of the ATRX gene revealed a downstream AUG start codon at residue 40, suggesting an alternative initiation event. Howard et al. (2004) suggested that 'phenotypic rescue' due to the expression of a truncated ATRX protein using the alternative downstream initiation site underlies the relatively mild phenotype seen in some patients with the R37X mutation. Abidi et al. (2005) identified the R37X mutation in 3 affected males originally reported by Chudley et al. (1988) as having Chudley-Lowry syndrome. Western blot and immunocytochemical analyses using a specific monoclonal antibody directed against ATRX showed the protein to be present in lymphoblastoid cells, despite the premature stop codon. Abidi et al. (2005) suggested that the less severe phenotype was due to the presence of some residual ATRX protein. The phenotypic variation between patients with the same mutation suggested that the ATRX gene may influence the expression of several genes in multiple tissues during development. (less)
not provided (-)	no classification provided Method: literature only	Alpha thalassemia-X-linked intellectual disability syndrome Affected status: yes Allele origin: germline	GeneReviews Accession: SCV000195529.2 First in ClinVar: Nov 25, 2014 Last updated: Oct 01, 2022	Publications: BookShelf: NBK1449 BookShelf: NBK1449
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Comment:

Stop-gained (nonsense): predicted to result in a loss or disruption of normal protein function through nonsense-mediated decay (NMD) or protein truncation. Multiple pathogenic variants are reported downstream of the variant (PVS1_VS). It is not observed in the gnomAD v2.1.1 dataset (PM2). The variant was observed as assumed (i.e. paternity and maternity not confirmed) de novoo (3billion dataset, PM6). The variant has been reported at least twice as pathogenic/likely pathogenic with clinical assertions and evidence for the classification (ClinVar ID: VCV000011742.7). Therefore, this variant is classified as pathogenic according to the recommendation of ACMG/AMP guideline.

Comment:

Segregates with X-linked intellectual disability, short stature, microcephaly, and dysmorphic features in multiple families; the heterozygous unaffected females showed skewed X-inactivation (Abidi et al., 2005; Basehore et al., 2015); Functional studies suggest that the variant may cause reduced protein expression compared to WT, however additional studies are needed to validate the impact of this variant on splicing (Howard et al., 2004); Nonsense variant predicted to result in protein truncation or nonsense mediated decay in a gene for which loss of function is a known mechanism of disease; Not observed at significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 25525159, 32170002, 3239563, 25606380, 18409179, 25167861, 25326635, 20301622, 28293299, 33173999, 25679214, 26147798, 31685013, 29491882, 26997013, 20865721, 32277047, 26350204, 30231518, 36031702, 12953102, 28152038, 31452935, 24805811, 10632111, 15508018, 32901917, 15591283)

Comment:

Studies have shown that this premature translational stop signal does not significantly alter or has an unclear effect on ATRX gene expression (PMID: 15508018, 15591283). For these reasons, this variant has been classified as Pathogenic. ClinVar contains an entry for this variant (Variation ID: 11742). This premature translational stop signal has been observed in individuals with clinical features of alpha-thalassemia X-linked intellectual disability syndrome (PMID: 10632111, 15508018, 24805811). It has also been observed to segregate with disease in related individuals. This variant is not present in population databases (gnomAD no frequency). This sequence change creates a premature translational stop signal (p.Arg37*) in the ATRX gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in ATRX are known to be pathogenic (PMID: 15591283, 18409179, 23681356).

Comment:

The p.R37* pathogenic mutation (also known as c.109C>T), located in coding exon 2 of the ATRX gene, results from a C to T substitution at nucleotide position 109. This changes the amino acid from an arginine to a stop codon within coding exon 2. This alteration has been shown to segregate with disease in several large families with variable intellectual disability (mild to profound), speech impairment, facial anomalies including +/- hypertelorism, short philtrum, open mouth, full lower lip, and microcephaly, growth deficiency, hypotonia, +/- seizures, +/- urogenital anomalies, and decreased Hgb H inclusions compared to most ATRX probands (Basehore MJ et al. Clin. Genet., 2015 May;87:461-6, Guerrini, R et al. Ann. Neurol. 2000;47(1):117-21, Moncini, S et al. Meta Gene 2013;1:102-108). This mutation is often observed to result in a less severe phenotype than is typically observed in patients with nonsense mutations in the ATRX gene, (Abidi, FE et al. Eur. J. Hum. Genet. 2005;13(2):176-83, Howard, MT et al. Med. Genet. 2004;41(12):951-6). Unaffected female carriers for this mutation have been observed to have highly skewed X-inactivation patterns of >90:10 (Abidi, FE et al. Eur. J. Hum. Genet. 2005;13(2):176-83, Basehore MJ et al. Clin. Genet., 2015 May;87:461-6). In addition to the clinical data presented in the literature, this alteration is expected to result in loss of function by premature protein truncation or nonsense-mediated mRNA decay. As such, this alteration is interpreted as a disease-causing mutation.

Comment:

Based on the classification scheme VCGS_Germline_v1.1.1, this variant is classified as Pathogenic. Following criteria are met: 0102 - Loss-of-function is a known mechanism of disease for this gene. (N) 0109 - This gene is known to be associated with both X-linked dominant and recessive disease (OMIM). (N) 0201 - Variant is predicted to cause nonsense-mediated decay (NMD) and loss of protein (exon 2 of 35). (P) 0253 - Variant is hemizygous. (N) 0301 - Variant is absent from gnomAD. (P) 0701 - Comparable variants have very strong previous evidence for pathogenicity. Many other NMD-predicted variants have previously been reported as pathogenic (ClinVar). (P) 0801 - Strong previous evidence of pathogenicity in unrelated individuals. The variant has been previously reported in more than 20 male patients with intellectual disability (ClinVar, PMID: 26350204, PMID: 24805811). (P) 0901 - Strong evidence for segregation with disease. The variant has been shown to segregate with disease in affected males in at least 5 families, with unaffected female carriers (PMID: 24805811). (P) 1102 - Strong phenotype match. (P) 1205 - Variant is maternally inherited. (N) Legend: (P) - Pathogenic, (N) - Neutral, (B) - Benign

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
Alpha-Thalassemia X-Linked Intellectual Disability Syndrome.	Adam MP	-	2020	PMID: 20301622
Targeted Next-Generation Sequencing Analysis of 1,000 Individuals with Intellectual Disability.	Grozeva D	Human mutation	2015	PMID: 26350204
Alpha-thalassemia intellectual disability: variable phenotypic expression among males with a recurrent nonsense mutation - c.109C>T (p.R37X).	Basehore MJ	Clinical genetics	2015	PMID: 24805811
Efficient strategy for the molecular diagnosis of intellectual disability using targeted high-throughput sequencing.	Redin C	Journal of medical genetics	2014	PMID: 25167861
Neuroradiologic features in X-linked α-thalassemia/mental retardation syndrome.	Wada T	AJNR. American journal of neuroradiology	2013	PMID: 23681356
Mutations in the chromatin-associated protein ATRX.	Gibbons RJ	Human mutation	2008	PMID: 18409179
Mutation in the 5' alternatively spliced region of the XNP/ATR-X gene causes Chudley-Lowry syndrome.	Abidi FE	European journal of human genetics : EJHG	2005	PMID: 15508018
Attenuation of an amino-terminal premature stop codon mutation in the ATRX gene by an alternative mode of translational initiation.	Howard MT	Journal of medical genetics	2004	PMID: 15591283
A nonsense mutation of the ATRX gene causing mild mental retardation and epilepsy.	Guerrini R	Annals of neurology	2000	PMID: 10632111
Carpenter-Waziri syndrome results from a mutation in XNP.	Abidi F	American journal of medical genetics	1999	PMID: 10398237
Mental retardation, distinct facial changes, short stature, obesity, and hypogonadism: a new X-linked mental retardation syndrome.	Chudley AE	American journal of medical genetics	1988	PMID: 3239563
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Text-mined citations for rs122445108 ...

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 Jan 19, 2025

ClinVar Genomic variation as it relates to human health

NM_000489.6(ATRX):c.109C>T (p.Arg37Ter)

Variant Details

Genes

Conditions - Germline

Submissions - Germline

Germline Functional Evidence

Citations for germline classification of this variant

Text-mined citations for rs122445108 ...