ClinVar Miner

Submissions for variant NM_000158.4(GBE1):c.1543C>T (p.Arg515Cys)

dbSNP: rs80338672
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Total submissions: 6
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Ambry Genetics RCV000210646 SCV000262898 pathogenic Inborn genetic diseases 2013-08-30 criteria provided, single submitter clinical testing
Invitae RCV001246690 SCV001420065 likely pathogenic Glycogen storage disease, type IV; Glycogen storage disease IV, classic hepatic 2019-10-02 criteria provided, single submitter clinical testing This sequence change replaces arginine with cysteine at codon 515 of the GBE1 protein (p.Arg515Cys). The arginine residue is highly conserved and there is a large physicochemical difference between arginine and cysteine. This variant is present in population databases (rs80338672, ExAC 0.02%). This variant has been observed in individuals affected with glycogen storage disease, also known as polyglucosan body myopathy (PMID: 8613547, 11949934). ClinVar contains an entry for this variant (Variation ID: 2779). This variant has been reported to affect GBE1 protein function (PMID: 8613547). This variant disrupts the p.Arg515 amino acid residue in GBE1. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 10762170, 24248152). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV000020161 SCV001983414 likely pathogenic Glycogen storage disease, type IV 2021-09-08 criteria provided, single submitter clinical testing Variant summary: GBE1 c.1543C>T (p.Arg515Cys) results in a non-conservative amino acid change located in the Glycosyl hydrolase, family 13, catalytic domain of the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 3.7e-05 in 243364 control chromosomes. c.1543C>T has been reported in the literature in individuals affected with Glycogen Storage Disease, Type IV (Bao_1996, Li_2010, Farwell_2015). These data indicate that the variant may be associated with disease. At least one publication reports experimental evidence evaluating an impact on protein function. The most pronounced variant effect results in 10%-<30% of normal activity (Bao_1996). One clinical diagnostic laboratory has submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation and classified the variant as likely pathogenic. In addition, p.R515H has been reported to associate with the disease too. Based on the evidence outlined above, the variant was classified as likely pathogenic.
Molecular Genetics, Royal Melbourne Hospital RCV000020161 SCV002503872 likely pathogenic Glycogen storage disease, type IV 2022-04-22 criteria provided, single submitter clinical testing This sequence change is predicted to replace arginine with cysteine at codon 515 of the GBE1 protein, p.(Arg515Cys). The arginine residue is highly conserved (100 vertebrates, UCSC), and is located within a helical region in the catalytic domain (PMID: 26199317). There is a large physicochemical difference between arginine and cysteine. The variant is present in a large population cohort at a frequency of 0.004%, which is consistent with recessive disease (rs80338672, 9/243,364 alleles, 0 homozygotes in gnomAD v2.1). It has been identified compound heterozygous with a second pathogenic allele or suspected compound heterozygous in cases with the fatal perinatal neuromuscular form or infantile classic hepatic phenotype of glycogen storage disorder type IV. Further, there was biochemical confirmation of the diagnosis in the cases with the classic hepatic phenotype, through the measurement of branching enzyme activity in patient fibroblasts (PMID: 8613547, 20058079, 26147564). Reduced enzymatic activity of the variant has also been demonstrated in i n vitro functional studies (PMID: 8613547). Multiple lines of computational evidence predict a deleterious effect for the missense substitution (7/7 algorithms). Additionally, a different missense change (p.Arg515His) at the same position, determined to be pathogenic has been identified in adult polyglucosan body disease (PMID: 10762170). Based on the classification scheme RMH ACMG Guidelines v1.2.1, this variant is classified as LIKELY PATHOGENIC . Following criteria are met: PM2, PM3, PM5, PS3_Supporting, PP3, PP4.
OMIM RCV000002910 SCV000023068 pathogenic Glycogen storage disease IV, classic hepatic 1996-02-15 no assertion criteria provided literature only
GeneReviews RCV000020161 SCV000040488 pathologic Glycogen storage disease, type IV 2009-04-02 no assertion criteria provided curation Converted during submission to Pathogenic.

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