Submissions for variant NM_005609.4(PYGM):c.2056G>A (p.Gly686Arg)

gnomAD frequency: 0.00006  dbSNP: rs144081869

Total submissions: 8

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Counsyl	RCV000002396	SCV000791243	likely pathogenic	Glycogen storage disease, type V	2017-05-05	criteria provided, single submitter	clinical testing
Invitae	RCV000002396	SCV000948122	pathogenic	Glycogen storage disease, type V	2024-01-09	criteria provided, single submitter	clinical testing	This sequence change replaces glycine, which is neutral and non-polar, with arginine, which is basic and polar, at codon 686 of the PYGM protein (p.Gly686Arg). This variant is present in population databases (rs144081869, gnomAD 0.009%). This missense change has been observed in individual(s) with glycogen storage disease type V (PMID: 9506549, 17404776). 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.Gly685Arg. ClinVar contains an entry for this variant (Variation ID: 2306). 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 95%. For these reasons, this variant has been classified as Pathogenic.
CeGaT Center for Human Genetics Tuebingen	RCV001091628	SCV001247779	pathogenic	not provided	2017-06-01	criteria provided, single submitter	clinical testing
GeneDx	RCV001091628	SCV004036928	likely pathogenic	not provided	2023-09-23	criteria provided, single submitter	clinical testing	Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 30560358, 9506549, 17404776, 25740218, 17217859, 29350794, 31179311, 32075227, 27303362, 34534370, 37091313)
PreventionGenetics, part of Exact Sciences	RCV003407258	SCV004115146	pathogenic	PYGM-related condition	2023-03-16	criteria provided, single submitter	clinical testing	The PYGM c.2056G>A variant is predicted to result in the amino acid substitution p.Gly686Arg. This variant has been reported in the compound heterozygous state with a second causative PYGM variant in several patients with histochemically or biochemically confirmed GSD V (Vorgerd et al. 1998. PubMed ID: 9506549, referred to as p.Gly685Arg; Deschauer et al. 2007. PubMed ID: 17404776). An additional patient was identified via use of the non-ischemic forearm exercise test, and was then found to be compound heterozygous for the c.2056G>A and c.148C>T (described above) variants (Hogrel et al. 2015. PubMed ID: 25740218). We have also observed this variant at PreventionGenetics, in the homozygous or compound heterozygous state, in two patients with suspected GSD V (internal data). This variant is reported in 0.0093% of alleles in individuals of European (Non-Finnish) descent in gnomAD (http://gnomad.broadinstitute.org/variant/11-64517969-C-T). This variant is interpreted as pathogenic.
Baylor Genetics	RCV000002396	SCV004207199	pathogenic	Glycogen storage disease, type V	2023-10-31	criteria provided, single submitter	clinical testing
OMIM	RCV000002396	SCV000022554	pathogenic	Glycogen storage disease, type V	1998-03-01	no assertion criteria provided	literature only
Practice for Gait Abnormalities, David Pomarino, Competency Network Toe Walking c/o Practice Pomarino	RCV003319973	SCV004023411	likely pathogenic	Tip-toe gait	2021-04-07	no assertion criteria provided	clinical testing