ClinVar Miner

Submissions for variant NM_005609.4(PYGM):c.613G>A (p.Gly205Ser) (rs119103251)

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Total submissions: 10
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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 2018-10-19 criteria provided, single submitter clinical testing The G205S missense change is the second most common pathogenic variant identified in the PYGMgene and accounts for about 10% of pathogenic variants in American patients and 9% of pathogenicalleles in Spanish patients with McArdle disease (glycogen storage disease type V) (Andreu et al.,2007). Functional studies demonstrate that the G205S variant results in undetectable PYGM proteinlevels (Birch et al., 2013). The G205S variant is a non-conservative amino acid substitution and occursat a position that is conserved across species. We interpret G205S as a pathogenic variant.
Invitae RCV000002389 SCV000752185 pathogenic Glycogen storage disease, type V 2020-10-31 criteria provided, single submitter clinical testing This sequence change replaces glycine with serine at codon 205 of the PYGM protein (p.Gly205Ser). The glycine residue is highly conserved and there is a small physicochemical difference between glycine and serine. This variant is present in population databases (rs119103251, ExAC 0.02%). This variant has been reported as homozygous or in combination with another pathogenic PYGM variant in multiple individuals affected with McArdle disease (PMID: 8316268, 19251976, 17221871, 17404776, 17630210). This finding is consistent with autosomal recessive inheritance, and suggests that this variant contributes to disease. This variant is also known as p.Gly204Ser in the literature. ClinVar contains an entry for this variant (Variation ID: 2299). Experimental studies have shown that this missense change causes a large reduction in protein expression and mislocalization of the protein to the nucleus (PMID: 22818872). For these reasons, this variant has been classified as Pathogenic.
EGL Genetic Diagnostics, Eurofins Clinical Diagnostics 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 2018-10-31 criteria provided, single submitter clinical testing
Illumina Clinical Services Laboratory,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.
OMIM RCV000002389 SCV000022547 pathogenic Glycogen storage disease, type V 2001-01-01 no assertion criteria provided literature only
GeneReviews RCV000002389 SCV000172196 pathogenic Glycogen storage disease, type V 2014-06-26 no assertion criteria 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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