ClinVar Miner

Submissions for variant NM_005609.4(PYGM):c.613G>A (p.Gly205Ser)

gnomAD frequency: 0.00027  dbSNP: rs119103251
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Total submissions: 12
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Counsyl RCV000002389 SCV000485126 pathogenic Glycogen storage disease, type V 2015-12-18 criteria provided, single submitter clinical testing
GeneDx RCV000414632 SCV000490759 pathogenic not provided 2021-03-02 criteria provided, single submitter clinical testing Functional studies demonstrate that the G205S variant results in undetectable PYGM protein levels (Birch et al., 2013); In silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect; This variant is associated with the following publications: (PMID: 10382912, 8316268, 31980526, 30316539, 30415384, 19433441, 17915571, 22818872, 25240406, 11706962, 10382911, 7603523, 19251976)
Invitae RCV000002389 SCV000752185 pathogenic Glycogen storage disease, type V 2024-01-26 criteria provided, single submitter clinical testing This sequence change replaces glycine, which is neutral and non-polar, with serine, which is neutral and polar, at codon 205 of the PYGM protein (p.Gly205Ser). This variant is present in population databases (rs119103251, gnomAD 0.02%). This missense change has been observed in individual(s) with McArdle disease (PMID: 8316268, 17221871, 17404776, 17630210, 19251976). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. This variant is also known as p.Gly204Ser. ClinVar contains an entry for this variant (Variation ID: 2299). 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 PYGM protein function with a positive predictive value of 80%. Experimental studies have shown that this missense change affects PYGM function (PMID: 22818872). For these reasons, this variant has been classified as Pathogenic.
Eurofins Ntd Llc (ga) RCV000414632 SCV000854833 pathogenic not provided 2015-11-04 criteria provided, single submitter clinical testing
Fulgent Genetics, Fulgent Genetics RCV000002389 SCV000893905 pathogenic Glycogen storage disease, type V 2022-02-10 criteria provided, single submitter clinical testing
Illumina Laboratory Services, Illumina RCV000002389 SCV000914531 pathogenic Glycogen storage disease, type V 2018-12-16 criteria provided, single submitter clinical testing Across a selection of available literature, the PYGM c.613G>A (p.Gly205Ser) missense variant has been reported in at least 14 homozygotes and 20 compound heterozygotes with glycogen storage disease type V (also known as McArdle disease) (Tsujino et al. 1993; Rubio et al. 2007; Lucia et al. 2012). Control data are unavailable for the p.Gly205Ser variant, which is reported at a frequency of 0.000349 in the European American population of the Exome sequencing project. In functional studies, overexpression of GFP-Gly205Ser-PYGM resulted in significant mislocalisation and aggregation of the altered protein to the perinuclear membrane region of CHO cells (Birch et al. 2013). Based on the collective evidence, the PYGM p.Gly205Ser variant is classified as pathogenic for glycogen storage disease type V. This variant was observed by ICSL as part of a predisposition screen in an ostensibly healthy population.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV000002389 SCV001519531 pathogenic Glycogen storage disease, type V 2021-03-09 criteria provided, single submitter clinical testing Variant summary: PYGM c.613G>A (p.Gly205Ser) results in a non-conservative amino acid change in 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 0.00012 in 251264 control chromosomes (gnomAD). This frequency is not significantly higher than expected for a pathogenic variant in PYGM causing Glycogen Storage Disease, Type V (0.00012 vs 0.0035), allowing no conclusion about variant significance. c.613G>A has been reported in the literature in multiple homozygous and compound heterozygous individuals affected with Glycogen Storage Disease, Type V (McArdle disease), and was described as the second most common pathogenic variant in the Caucasian population (see e.g. Tsujino_1993, Martin_2001, Vieitez_2011). These data indicate that the variant is very likely to be associated with disease. At least one publication reported experimental evidence evaluating an impact on protein function, and demonstrated that the variant results in decreased protein expression, together with an extensive aggregation of the variant protein in the perinuclear region (Birch_2012). Seven clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All laboratories classified the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic.
Revvity Omics, Revvity Omics RCV000002389 SCV002019581 pathogenic Glycogen storage disease, type V 2023-03-16 criteria provided, single submitter clinical testing
Baylor Genetics RCV000002389 SCV004207198 pathogenic Glycogen storage disease, type V 2023-10-31 criteria provided, single submitter clinical testing
OMIM RCV000002389 SCV000022547 pathogenic Glycogen storage disease, type V 2001-01-01 no assertion criteria provided literature only
GeneReviews RCV000002389 SCV000172196 not provided Glycogen storage disease, type V no assertion provided literature only
Natera, Inc. RCV000002389 SCV001454301 pathogenic Glycogen storage disease, type V 2020-09-16 no assertion criteria provided clinical testing

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