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

dbSNP: rs80338672

Total submissions: 7

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	pathogenic	Glycogen storage disease, type IV; Glycogen storage disease IV, classic hepatic	2023-11-05	criteria provided, single submitter	clinical testing	This sequence change replaces arginine, which is basic and polar, with cysteine, which is neutral and slightly polar, at codon 515 of the GBE1 protein (p.Arg515Cys). This variant is present in population databases (rs80338672, gnomAD 0.01%). This missense change has been observed in individual(s) with glycogen storage disease, also known as polyglucosan body myopathy (PMID: 8613547, 11949934). ClinVar contains an entry for this variant (Variation ID: 2779). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is expected to disrupt GBE1 protein function with a positive predictive value of 95%. Experimental studies have shown that this missense change affects GBE1 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. For these reasons, this variant has been classified as 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.
Baylor Genetics	RCV000020161	SCV004198664	pathogenic	Glycogen storage disease, type IV	2023-10-17	criteria provided, single submitter	clinical testing
OMIM	RCV000002910	SCV000023068	pathogenic	Glycogen storage disease IV, classic hepatic	1996-02-15	no assertion criteria provided	literature only
GeneReviews	RCV000020161	SCV000040488	not provided	Glycogen storage disease, type IV		no assertion provided	literature only