VCV000002791.7 - ClinVar

NM_000158.4(GBE1):c.784C>T (p.Arg262Cys)

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.

(5)

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
Pathogenic(1); Likely pathogenic(1); Uncertain significance(2)

criteria provided, conflicting classifications

Somatic

No data submitted for somatic clinical impact

Somatic

No data submitted for oncogenicity

Variant Details

Identifiers

NM_000158.4(GBE1):c.784C>T (p.Arg262Cys)

Variation ID: 2791 Accession: VCV000002791.7

Type and length

single nucleotide variant, 1 bp

Location

Cytogenetic: 3p12.2 3: 81642989 (GRCh38) [ NCBI UCSC ] 3: 81692140 (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	Aug 28, 2017	Jun 17, 2024	Feb 23, 2024

HGVS

Nucleotide	Protein	Molecular consequence
NM_000158.4:c.784C>T MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.	NP_000149.4:p.Arg262Cys	missense
NC_000003.12:g.81642989G>A
NC_000003.11:g.81692140G>A
NG_011810.1:g.123812C>T

Protein change

R262C

Other names

NM_000158.4(GBE1):c.784C>T
p.Arg262Cys

Canonical SPDI

NC_000003.12:81642988: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.

Trans-Omics for Precision Medicine (TOPMed) 0.00000

The Genome Aggregation Database (gnomAD), exomes 0.00001

Exome Aggregation Consortium (ExAC) 0.00003

Links

ClinGen: CA115764 OMIM: 607839.0016 dbSNP: rs137852893 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.
GBE1		-	-	GRCh38 GRCh37	1008	1024

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.
Glycogen storage disease due to glycogen branching enzyme deficiency, congenital neuromuscular form	Pathogenic (1)	no assertion criteria provided	Apr 15, 2006	RCV000002925.4
Adult polyglucosan body disease	Pathogenic (1)	criteria provided, single submitter	Nov 15, 2016	RCV000501317.1
Glycogen storage disease, type IV	Conflicting interpretations of pathogenicity (2)	criteria provided, conflicting classifications	Feb 23, 2024	RCV001826408.5
Glycogen storage disease IV, classic hepatic Glycogen storage disease, type IV	Uncertain significance (1)	criteria provided, single submitter	Aug 4, 2022	RCV002512687.2

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.
Pathogenic (Nov 15, 2016)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Adult polyglucosan body disease Affected status: yes Allele origin: maternal	Center of Genomic medicine, Geneva, University Hospital of Geneva Accession: SCV000598137.1 First in ClinVar: Aug 28, 2017 Last updated: Aug 28, 2017	Comment: This heterozygous variant in the GBE1 gene (autosomal recessive transmission), inherited from the mother, was present in a female patient who also harbours a second … (more) This heterozygous variant in the GBE1 gene (autosomal recessive transmission), inherited from the mother, was present in a female patient who also harbours a second variant in the same codon of same gene inherited by the father (compound heterozygosity). (less) Age: 40-49 years Sex: female
Uncertain significance (Jan 27, 2022)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: curation	Glycogen storage disease, type IV (Autosomal recessive inheritance) Affected status: unknown Allele origin: germline	Broad Center for Mendelian Genomics, Broad Institute of MIT and Harvard Accession: SCV002097114.1 First in ClinVar: Feb 13, 2022 Last updated: Feb 13, 2022	Comment: The p.Arg262Cys variant in GBE1 has been reported in 1 individual, in the compound heterozygous state, with glycogen storage disease type IV (GSD IV) (PMID: … (more) The p.Arg262Cys variant in GBE1 has been reported in 1 individual, in the compound heterozygous state, with glycogen storage disease type IV (GSD IV) (PMID: 16528737) and has been identified in 0.003% (3/103974) of European (non-Finnish) chromosomes by the Genome Aggregation Database (gnomAD, http://gnomad.broadinstitute.org; dbSNP ID: rs137852893). Although this variant has been seen in the general population in a heterozygous state, its frequency is low enough to be consistent with a recessive carrier frequency. This variant has also been reported in ClinVar (Variation ID#: 2791) and has been interpreted as pathogenic by OMIM and Center of Genomic medicine (Geneva, University Hospital of Geneva). Computational prediction tools and conservation analyses suggest that this variant may impact the protein, though this information is not predictive enough to determine pathogenicity. The phenotype of an individual compound heterozygous for this variant is highly specific for GSD IV based on strict biochemical investigations consistent with disease (PMID: 16528737). In summary, the clinical significance of the p.Arg262Cys variant is uncertain. ACMG/AMP Criteria applied: PP3, PM2_supporting, PP4 (Richards 2015). (less)
Uncertain significance (Aug 04, 2022)	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015)) Method: clinical testing	Glycogen storage disease, type IV Glycogen storage disease IV, classic hepatic Affected status: unknown Allele origin: germline	Labcorp Genetics (formerly Invitae), Labcorp Accession: SCV003525253.1 First in ClinVar: Feb 07, 2023 Last updated: Feb 07, 2023	Publications: PubMed (1) PubMed: 16528737 Comment: This sequence change replaces arginine, which is basic and polar, with cysteine, which is neutral and slightly polar, at codon 262 of the GBE1 protein … (more) This sequence change replaces arginine, which is basic and polar, with cysteine, which is neutral and slightly polar, at codon 262 of the GBE1 protein (p.Arg262Cys). This variant is present in population databases (rs137852893, gnomAD 0.003%). This missense change has been observed in individual(s) with glycogen storage disease (PMID: 16528737). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. ClinVar contains an entry for this variant (Variation ID: 2791). Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Not Available"; PolyPhen-2: "Probably Damaging"; Align-GVGD: "Not Available"). 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)
Likely pathogenic (Feb 23, 2024)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Glycogen storage disease, type IV Affected status: unknown Allele origin: unknown	Baylor Genetics Accession: SCV004198681.2 First in ClinVar: Dec 30, 2023 Last updated: Jun 17, 2024
Pathogenic (Apr 15, 2006)	no assertion criteria provided Method: literature only	GLYCOGEN STORAGE DISEASE IV, CONGENITAL NEUROMUSCULAR Affected status: not provided Allele origin: germline	OMIM Accession: SCV000023083.3 First in ClinVar: Apr 04, 2013 Last updated: Dec 31, 2022	Publications: PubMed (1) PubMed: 16528737 Comment on evidence: For discussion of the 784C-T transition in the GBE1 gene, resulting in an arg262-to-cys (R262C) substitution, that was identified in compound heterozygous state in a … (more) For discussion of the 784C-T transition in the GBE1 gene, resulting in an arg262-to-cys (R262C) substitution, that was identified in compound heterozygous state in a patient with glycogen storage disease IV (GSD4; 232500) by Burrow et al. (2006), see 607839.0015. (less)

Comment:

This heterozygous variant in the GBE1 gene (autosomal recessive transmission), inherited from the mother, was present in a female patient who also harbours a second variant in the same codon of same gene inherited by the father (compound heterozygosity).

Comment:

The p.Arg262Cys variant in GBE1 has been reported in 1 individual, in the compound heterozygous state, with glycogen storage disease type IV (GSD IV) (PMID: 16528737) and has been identified in 0.003% (3/103974) of European (non-Finnish) chromosomes by the Genome Aggregation Database (gnomAD, http://gnomad.broadinstitute.org; dbSNP ID: rs137852893). Although this variant has been seen in the general population in a heterozygous state, its frequency is low enough to be consistent with a recessive carrier frequency. This variant has also been reported in ClinVar (Variation ID#: 2791) and has been interpreted as pathogenic by OMIM and Center of Genomic medicine (Geneva, University Hospital of Geneva). Computational prediction tools and conservation analyses suggest that this variant may impact the protein, though this information is not predictive enough to determine pathogenicity. The phenotype of an individual compound heterozygous for this variant is highly specific for GSD IV based on strict biochemical investigations consistent with disease (PMID: 16528737). In summary, the clinical significance of the p.Arg262Cys variant is uncertain. ACMG/AMP Criteria applied: PP3, PM2_supporting, PP4 (Richards 2015).

Comment:

This sequence change replaces arginine, which is basic and polar, with cysteine, which is neutral and slightly polar, at codon 262 of the GBE1 protein (p.Arg262Cys). This variant is present in population databases (rs137852893, gnomAD 0.003%). This missense change has been observed in individual(s) with glycogen storage disease (PMID: 16528737). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. ClinVar contains an entry for this variant (Variation ID: 2791). Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Not Available"; PolyPhen-2: "Probably Damaging"; Align-GVGD: "Not Available"). 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.

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
Non-lethal congenital hypotonia due to glycogen storage disease type IV.	Burrow TA	American journal of medical genetics. Part A	2006	PMID: 16528737

Text-mined citations for rs137852893 ...

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 Sep 29, 2024

ClinVar Genomic variation as it relates to human health

NM_000158.4(GBE1):c.784C>T (p.Arg262Cys)

Variant Details

Genes

Conditions - Germline

Submissions - Germline

Germline Functional Evidence

Citations for germline classification of this variant

Text-mined citations for rs137852893 ...