Submissions for variant NM_005609.4(PYGM):c.1805G>A (p.Arg602Gln)

gnomAD frequency: 0.00009  dbSNP: rs373190458

Total submissions: 10

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Eurofins Ntd Llc (ga)	RCV000727737	SCV000855109	uncertain significance	not provided	2018-04-23	criteria provided, single submitter	clinical testing
Illumina Laboratory Services, Illumina	RCV000779073	SCV000915542	uncertain significance	Glycogen storage disease, type V	2017-05-18	criteria provided, single submitter	clinical testing	The PYGM c.1805G>A (p.Arg602Gln) missense variant has been reported in one study in which it is identified in a compound heterozygous state with a stop-gained variant in one individual with glycogen storage disease type V (Hadjigeorgiou et al. 2002). Family studies revealed that the patient’s unaffected mother was heterozygous for the p.Arg602Gln variant, while the affected father was homozygous for the stop-gained variant. The p.Arg602Gln variant was absent from 60 control individuals and is reported at a frequency of 0.00021 in the European (non-Finnish) population of the Exome Aggregation Consortium. The evidence for this variant is limited. Therefore, the p.Arg602Gln variant is classified as a variant of unknown significance, but suspicious for pathogenicity for glycogen storage disease type V. This variant was observed by ICSL as part of a predisposition screen in an ostensibly healthy population.
CeGaT Center for Human Genetics Tuebingen	RCV000727737	SCV001247781	pathogenic	not provided	2019-10-01	criteria provided, single submitter	clinical testing
GeneDx	RCV000727737	SCV001819482	pathogenic	not provided	2021-03-02	criteria provided, single submitter	clinical testing	Missense variants in this gene are often considered pathogenic (Stenson et al., 2014); 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: 17915571, 21658951, 15979037, 21880526, 12398832, 25741863)
Practice for Gait Abnormalities, David Pomarino, Competency Network Toe Walking c/o Practice Pomarino	RCV002221250	SCV002498558	likely pathogenic	Tip-toe gait	2022-03-31	criteria provided, single submitter	clinical testing	Toe Walking has various causes, ranging from idiopathic or habitual reasons to an underlying neuromuscular disease. The most observed form of toe walking is idiopathic toe walking (ITW) - a diagnosis of exclusion. ITW occurs in about 5% of children after their second birthday and is a common problem in pediatric orthopedics. In about 70% of these cases, there is spontaneous remission within six months of the onset of ITW. If the toe walk persists, one can assume the presence of a non-idiopathic form of toe walk (n-ITW). In n-ITW, the causes of the abnormal gait are neurological or myogenic. Differential diagnoses such as infantile cerebral palsy, muscular dystrophy, spinal amyotrophy and hereditary motor-sensory neuropathy as well as rare metabolic disorders of the musculature must be considered (Pomarino et al., 2018). In our clinical ITW consultation, we screen children with n-ITW for a genetic form of tiptoe gait using next generation sequencing for gene variants in 49 genes. These are genes in which gene variants can lead to neuromuscular diseases in which an association with toe-tapping gait has been reported or can be suspected due to patients’ clinical symptoms. To the best of our knowledge, this is the first study in which several patients with toe walking displayed heterozygosity for pathogenic or likely pathogenic PYGM mutations and mild symptoms of the metabolic muscle disease McArdle. The findings of our research are in line with recently published observations in heterozygous family members patients with McArdle disease. We should mention that some of the patients in our cohort harbored heterozygous variants in other genes of our gene panel. However, the numbers in this study were too small to workout any resulting combined genetic effects. It is concluded that genetic conditions can contribute to the development of toe walking. Apparently, even a slight genetic weakening of the muscles can lead to changes to the gait pattern. Future studies must show how the pathomechanism can be explained for the PYGM variants and whether there are new therapeutic approaches to be developed based on this research.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000779073	SCV002570793	likely pathogenic	Glycogen storage disease, type V	2022-07-21	criteria provided, single submitter	clinical testing	Variant summary: PYGM c.1805G>A (p.Arg602Gln) results in a conservative amino acid change in the encoded protein sequence. Four of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 0.00014 in 251210 control chromosomes. This frequency is not significantly higher than expected for a pathogenic variant in PYGM causing Glycogen Storage Disease, Type V (0.00014 vs 0.0035), allowing no conclusion about variant significance. c.1805G>A has been reported in the literature in individuals affected with Glycogen Storage Disease, Type V. These data indicate that the variant may be associated with disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Five clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. Multiple laboratories reported the variant with conflicting assessments (pathogenic n=2, likely pathogenic n=1, VUS n=2). In addition, R602W has been reported to associate with Glycogen Storage Disease, Type V (McArdle disease, HGMD database). Based on the evidence outlined above, the variant was classified as likely pathogenic.
Labcorp Genetics (formerly Invitae), Labcorp	RCV000779073	SCV003523896	pathogenic	Glycogen storage disease, type V	2024-01-05	criteria provided, single submitter	clinical testing	This sequence change replaces arginine, which is basic and polar, with glutamine, which is neutral and polar, at codon 602 of the PYGM protein (p.Arg602Gln). This variant is present in population databases (rs373190458, gnomAD 0.3%). This missense change has been observed in individual(s) with McArdle disease (PMID: 12398832, 21658951, 21880526, 34215481). 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 Arg601Gln. ClinVar contains an entry for this variant (Variation ID: 592764). 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) has been performed at Invitae for this missense variant, however the output from this modeling did not meet the statistical confidence thresholds required to predict the impact of this variant on PYGM protein function. Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. This variant disrupts the p.Arg602 amino acid residue in PYGM. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 22250184; Invitae). 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.
Revvity Omics, Revvity	RCV000779073	SCV003818081	uncertain significance	Glycogen storage disease, type V	2022-12-22	criteria provided, single submitter	clinical testing
Baylor Genetics	RCV000779073	SCV004041141	likely pathogenic	Glycogen storage disease, type V	2024-03-20	criteria provided, single submitter	clinical testing
PreventionGenetics, part of Exact Sciences	RCV003420284	SCV004118277	pathogenic	PYGM-related disorder	2024-03-07	no assertion criteria provided	clinical testing	The PYGM c.1805G>A variant is predicted to result in the amino acid substitution p.Arg602Gln. This variant has been reported in the biallelic state in multiple patients with McArdle disease (Hadjigeorgiou et al 2002. PubMed ID: 12398832; variant referred to as p.Arg601Gln in Miteff et al. 2011. PubMed ID: 21658951; Gandhi et al. 2021. PubMed ID: 34215481; Pizzamiglio et al. 2021. PubMed ID: 34534370). This variant is reported in 0.25% of alleles in individuals of Ashkenazi Jewish descent in gnomAD. In addition, another variant impacting the same amino acid (p.Arg602Trp) has been reported in a patient with McArdle disease (Lucia et al. 2012. PubMed ID: 22250184). Based on this evidence, we interpret the c.1805G>A (p.Arg602Gln) variant as pathogenic.