VCV000285961.34 - ClinVar

NM_000232.5(SGCB):c.496A>G (p.Ile166Val)

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.

(12)

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
Uncertain significance(9); Likely benign(1)

criteria provided, conflicting classifications

Somatic

No data submitted for somatic clinical impact

Somatic

No data submitted for oncogenicity

Variant Details

Identifiers

NM_000232.5(SGCB):c.496A>G (p.Ile166Val)

Variation ID: 285961 Accession: VCV000285961.34

Type and length

single nucleotide variant, 1 bp

Location

Cytogenetic: 4q12 4: 52028855 (GRCh38) [ NCBI UCSC ] 4: 52895021 (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	Dec 6, 2016	Jan 19, 2025	Mar 1, 2024

HGVS

Nucleotide	Protein	Molecular consequence
NM_000232.5:c.496A>G MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.	NP_000223.1:p.Ile166Val	missense
NC_000004.12:g.52028855T>C
NC_000004.11:g.52895021T>C
NG_008891.1:g.14465A>G
LRG_204:g.14465A>G
LRG_204t1:c.496A>G	LRG_204p1:p.Ile166Val

... more HGVS ... less HGVS

Protein change

I166V

Other names

Canonical SPDI

NC_000004.12:52028854:T:C

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.

The Genome Aggregation Database (gnomAD) 0.00028

Trans-Omics for Precision Medicine (TOPMed) 0.00029

The Genome Aggregation Database (gnomAD), exomes 0.00037

Exome Aggregation Consortium (ExAC) 0.00044

NHLBI Exome Sequencing Project (ESP) Exome Variant Server 0.00054

Links

ClinGen: CA2918377 dbSNP: rs138877636 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.
SGCB		-	-	GRCh38 GRCh37	500	611

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.
not specified	Likely benign (1)	criteria provided, single submitter	Feb 6, 2024	RCV000286709.4
Autosomal recessive limb-girdle muscular dystrophy type 2E	Uncertain significance (5)	criteria provided, multiple submitters, no conflicts	Jun 22, 2023	RCV000696139.11
not provided	Uncertain significance (4)	criteria provided, multiple submitters, no conflicts	Mar 1, 2024	RCV000725755.20
Qualitative or quantitative defects of beta-sarcoglycan	Uncertain significance (1)	criteria provided, single submitter	Jan 12, 2018	RCV001148509.4
Inborn genetic diseases	Uncertain significance (1)	criteria provided, single submitter	Apr 28, 2022	RCV002519200.2

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.
Uncertain significance (Jul 10, 2018)	criteria provided, single submitter (EGL ClinVar v180209 classification definitions) Method: clinical testing	not provided Affected status: unknown Allele origin: germline	Eurofins Ntd Llc (ga) Accession: SCV000339197.4 First in ClinVar: Dec 06, 2016 Last updated: Dec 15, 2018	Other databases http://www.egl-eurofins.com/emvc… http://www.egl-eurofins.com/emvclass/emvclass.php?approved_symbol=SGCB Number of individuals with the variant: 8 Zygosity: Single Heterozygote Sex: mixed
Uncertain significance (Aug 30, 2018)	criteria provided, single submitter (GeneDx Variant Classification (06012015)) Method: clinical testing	Not Provided Affected status: yes Allele origin: germline	GeneDx Accession: SCV000565558.3 First in ClinVar: Dec 06, 2016 Last updated: Dec 06, 2016	Comment: A variant of uncertain significance has been identified in the SGCB gene. The I166V variant has not been published as a pathogenic variant, nor has … (more) A variant of uncertain significance has been identified in the SGCB gene. The I166V variant has not been published as a pathogenic variant, nor has it been reported as a benign variant to our knowledge. It was not observed with any significant frequency in approximately 6,500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project. The I166V variant is a conservative amino acid substitution, which is not likely to impact secondary protein structure as these residues share similar properties. This substitution occurs at a position where amino acids with similar properties to Isoleucine are tolerated across species. However, in silico analysis is inconsistent in its predictions as to whether or not the variant is damaging to the protein structure/function. Therefore, based on the currently available information, it is unclear whether this variant is a pathogenic variant or a rare benign variant. (less)
Uncertain significance (Jan 12, 2018)	criteria provided, single submitter (ICSL Variant Classification Criteria 13 December 2019) Method: clinical testing	Qualitative or quantitative defects of beta-sarcoglycan Affected status: unknown Allele origin: germline	Illumina Laboratory Services, Illumina Accession: SCV001309408.1 First in ClinVar: May 31, 2020 Last updated: May 31, 2020	Comment: This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated … (more) This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score, this variant could not be ruled out of causing disease and therefore its association with disease required further investigation. A literature search was performed for the gene, cDNA change, and amino acid change (if applicable). No publications were found based on this search. This variant was therefore classified as a variant of unknown significance for this disease. (less)
Uncertain significance (Nov 10, 2021)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Autosomal recessive limb-girdle muscular dystrophy type 2E Affected status: unknown Allele origin: unknown	Fulgent Genetics, Fulgent Genetics Accession: SCV002816638.1 First in ClinVar: Dec 31, 2022 Last updated: Dec 31, 2022
Uncertain significance (Oct 24, 2022)	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015)) Method: clinical testing	Autosomal recessive limb-girdle muscular dystrophy type 2E Affected status: unknown Allele origin: germline	Labcorp Genetics (formerly Invitae), Labcorp Accession: SCV000824687.4 First in ClinVar: Oct 10, 2018 Last updated: Feb 07, 2023	Publications: PubMed (1) PubMed: 28492532 Comment: This sequence change replaces isoleucine, which is neutral and non-polar, with valine, which is neutral and non-polar, at codon 166 of the SGCB protein (p.Ile166Val). … (more) This sequence change replaces isoleucine, which is neutral and non-polar, with valine, which is neutral and non-polar, at codon 166 of the SGCB protein (p.Ile166Val). This variant is present in population databases (rs138877636, gnomAD 0.07%). This variant has not been reported in the literature in individuals affected with SGCB-related conditions. ClinVar contains an entry for this variant (Variation ID: 285961). Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be tolerated. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. (less)
Uncertain significance (May 25, 2023)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Not provided Affected status: unknown Allele origin: germline	Mayo Clinic Laboratories, Mayo Clinic Accession: SCV001714111.2 First in ClinVar: Jun 15, 2021 Last updated: Jan 26, 2024	Comment: BP4 Number of individuals with the variant: 3
Uncertain significance (Jun 22, 2023)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Autosomal recessive limb-girdle muscular dystrophy type 2E Affected status: unknown Allele origin: germline	Revvity Omics, Revvity Accession: SCV003827632.2 First in ClinVar: Mar 04, 2023 Last updated: Feb 04, 2024
Uncertain significance (Apr 28, 2022)	criteria provided, single submitter (Ambry Variant Classification Scheme 2023) Method: clinical testing	Inborn genetic diseases Affected status: unknown Allele origin: germline	Ambry Genetics Accession: SCV003679105.2 First in ClinVar: Feb 07, 2023 Last updated: May 01, 2024	Comment: The c.496A>G (p.I166V) alteration is located in exon 4 (coding exon 4) of the SGCB gene. This alteration results from a A to G substitution … (more) The c.496A>G (p.I166V) alteration is located in exon 4 (coding exon 4) of the SGCB gene. This alteration results from a A to G substitution at nucleotide position 496, causing the isoleucine (I) at amino acid position 166 to be replaced by a valine (V). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. (less)
Uncertain significance (Mar 01, 2024)	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: SCV004150629.11 First in ClinVar: Nov 20, 2023 Last updated: Dec 22, 2024	Number of individuals with the variant: 2
likely benign (Feb 06, 2024)	criteria provided, single submitter (Athena Diagnostics Criteria) Method: clinical testing	not specified Affected status: unknown Allele origin: unknown	Athena Diagnostics Accession: SCV000615220.2 First in ClinVar: Dec 06, 2016 Last updated: Jan 19, 2025
Uncertain significance (Apr 21, 2020)	no assertion criteria provided Method: clinical testing	Limb-girdle muscular dystrophy type 2E Affected status: unknown Allele origin: germline	Natera, Inc. Accession: SCV001462205.1 First in ClinVar: Jan 02, 2021 Last updated: Jan 02, 2021
not provided (-)	no classification provided Method: phenotyping only	Autosomal recessive limb-girdle muscular dystrophy type 2E Affected status: unknown Allele origin: unknown	GenomeConnect - Invitae Patient Insights Network Accession: SCV001749850.1 First in ClinVar: Jul 18, 2021 Last updated: Jul 18, 2021	Comment: Variant interpreted as Uncertain significance and reported on 04-21-2020 by Invitae. GenomeConnect-Invitae Patient Insights Network assertions are reported exactly as they appear on the patient-provided … (more) Variant interpreted as Uncertain significance and reported on 04-21-2020 by Invitae. GenomeConnect-Invitae Patient Insights Network assertions are reported exactly as they appear on the patient-provided report from the testing laboratory. Registry team members make no attempt to reinterpret the clinical significance of the variant. Phenotypic details are available under supporting information. (less) Clinical Features: Myopia (present) , Abnormal intestine morphology (present) , Abnormal muscle physiology (present) , Abnormality of urine homeostasis (present) , Anxiety (present) , Depression (present) , … (more) Myopia (present) , Abnormal intestine morphology (present) , Abnormal muscle physiology (present) , Abnormality of urine homeostasis (present) , Anxiety (present) , Depression (present) , Compulsive behaviors (present) , Abnormal delivery (present) (less) Indication for testing: Diagnostic Age: 20-29 years Sex: male Testing laboratory: Invitae Date variant was reported to submitter: 2020-04-21 Testing laboratory interpretation: Uncertain significance
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Comment:

A variant of uncertain significance has been identified in the SGCB gene. The I166V variant has not been published as a pathogenic variant, nor has it been reported as a benign variant to our knowledge. It was not observed with any significant frequency in approximately 6,500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project. The I166V variant is a conservative amino acid substitution, which is not likely to impact secondary protein structure as these residues share similar properties. This substitution occurs at a position where amino acids with similar properties to Isoleucine are tolerated across species. However, in silico analysis is inconsistent in its predictions as to whether or not the variant is damaging to the protein structure/function. Therefore, based on the currently available information, it is unclear whether this variant is a pathogenic variant or a rare benign variant.

Comment:

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score, this variant could not be ruled out of causing disease and therefore its association with disease required further investigation. A literature search was performed for the gene, cDNA change, and amino acid change (if applicable). No publications were found based on this search. This variant was therefore classified as a variant of unknown significance for this disease.

Comment:

This sequence change replaces isoleucine, which is neutral and non-polar, with valine, which is neutral and non-polar, at codon 166 of the SGCB protein (p.Ile166Val). This variant is present in population databases (rs138877636, gnomAD 0.07%). This variant has not been reported in the literature in individuals affected with SGCB-related conditions. ClinVar contains an entry for this variant (Variation ID: 285961). Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be tolerated. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance.

Comment:

The c.496A>G (p.I166V) alteration is located in exon 4 (coding exon 4) of the SGCB gene. This alteration results from a A to G substitution at nucleotide position 496, causing the isoleucine (I) at amino acid position 166 to be replaced by a valine (V). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear.

Comment:

Variant interpreted as Uncertain significance and reported on 04-21-2020 by Invitae. GenomeConnect-Invitae Patient Insights Network assertions are reported exactly as they appear on the patient-provided report from the testing laboratory. Registry team members make no attempt to reinterpret the clinical significance of the variant. Phenotypic details are available under supporting information.

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
http://www.egl-eurofins.com/emvclass/emvclass.php?approved_symbol=SGCB	-	-	-	-

Text-mined citations for rs138877636 ...

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_000232.5(SGCB):c.496A>G (p.Ile166Val)

Variant Details

Genes

Conditions - Germline

Submissions - Germline

Germline Functional Evidence

Citations for germline classification of this variant

Text-mined citations for rs138877636 ...