Submissions for variant NM_005609.4(PYGM):c.1537A>G (p.Ile513Val)

gnomAD frequency: 0.00232  dbSNP: rs139570786

Total submissions: 12

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Eurofins Ntd Llc (ga)	RCV000675632	SCV000225874	uncertain significance	not provided	2018-08-16	criteria provided, single submitter	clinical testing
GeneDx	RCV000675632	SCV000567874	likely benign	not provided	2021-03-30	criteria provided, single submitter	clinical testing	This variant is associated with the following publications: (PMID: 26907767, 32420686, 24503134, 23653251, 25741863, 25214167, 30560358)
Mayo Clinic Laboratories, Mayo Clinic	RCV000675632	SCV000801333	uncertain significance	not provided	2023-02-21	criteria provided, single submitter	clinical testing
Labcorp Genetics (formerly Invitae), Labcorp	RCV000509394	SCV000835576	uncertain significance	Glycogen storage disease, type V	2022-10-18	criteria provided, single submitter	clinical testing	This sequence change replaces isoleucine with valine at codon 513 of the PYGM protein (p.Ile513Val). The isoleucine residue is highly conserved and there is a small physicochemical difference between isoleucine and valine. This variant is present in population databases (rs139570786, gnomAD 0.7%), and has an allele count higher than expected for a pathogenic variant. This missense change has been observed in individual(s) with McArdle disease (PMID: 23653251; Invitae). ClinVar contains an entry for this variant (Variation ID: 194233). 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 not expected to disrupt PYGM protein function. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance.
CeGaT Center for Human Genetics Tuebingen	RCV000675632	SCV001247783	likely benign	not provided	2024-05-01	criteria provided, single submitter	clinical testing	PYGM: BS2
Pars Genome Lab	RCV000509394	SCV001652841	likely benign	Glycogen storage disease, type V	2021-05-18	criteria provided, single submitter	clinical testing
Genome-Nilou Lab	RCV000509394	SCV001806529	likely benign	Glycogen storage disease, type V	2021-07-22	criteria provided, single submitter	clinical testing
Practice for Gait Abnormalities, David Pomarino, Competency Network Toe Walking c/o Practice Pomarino	RCV001849178	SCV002106402	likely pathogenic	Tip-toe gait	2021-05-31	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	RCV003330533	SCV004038505	likely benign	not specified	2023-08-09	criteria provided, single submitter	clinical testing	Variant summary: PYGM c.1537A>G (p.Ile513Val) results in a conservative amino acid change in the encoded protein sequence. Four of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 0.003 in 251172 control chromosomes, predominantly at a frequency of 0.0037 within the Non-Finnish European subpopulation, and is found in 2 homozygotes in the gnomAD database. The observed variant frequency in the gnomAD database is approximately equal to the estimated maximal expected allele frequency for a pathogenic variant in PYGM causing Glycogen Storage Disease, Type V phenotype (0.0035), suggesting that the variant may be a benign polymorphism. c.1537A>G has been reported in the literature as a compound heterozygous genotype in at least three individuals affected with Glycogen Storage Disease, Type V (e.g. Gurgel-Giannetti_2013, Zare_2022); however, two of these individuals were siblings who also had the variant in cis with a variant of uncertain significance (Zare_2022). The variant was also reported in the compound heterozygous state following multigene panel testing in an individual with limb-girdle muscular dystrophy who had a clinical diagnosis with histology showing dystrophic features (Savarese_2014). These reports do not provide unequivocal conclusions about association of the variant with Glycogen Storage Disease, Type V. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. The following publications have been ascertained in the context of this evaluation (PMID: 23653251, 25214167, PMCID: PMC9627962). Nine submitters have cited clinical-significance assessments for this variant to ClinVar after 2014. Multiple submitters reported the variant with conflicting assessments: benign/likely benign (n=5), VUS (n=3), likely patogenic (n=1). Based on the evidence outlined above, the variant was classified as likely benign.
PreventionGenetics, part of Exact Sciences	RCV003430725	SCV004116704	uncertain significance	PYGM-related disorder	2022-10-25	criteria provided, single submitter	clinical testing	The PYGM c.1537A>G variant is predicted to result in the amino acid substitution p.Ile513Val. This variant has been previously detected, in the heterozygous state with one other known pathogenic PYGM variant, in at least two unrelated patients with glycogen storage disease type V (GSD V, also known as McArdle Disease) (Gurgel-Giannetti et al. 2013. PubMed ID: 23653251; Savarese et al. 2014. PubMed ID: 25214167). In the patient reported by Gurgel-Giannetti et al., it was confirmed to be in trans with a known pathogenic variant. However, this variant is also reported at a minor allele frequency ranging from 0.12% to 0.65% in multiple populations in gnomAD, which may indicate this variant is too common to be a primary cause of disease (http://gnomad.broadinstitute.org/variant/11-64519958-T-C). This variant is reported with interpretations ranging from benign to uncertain in the ClinVar database (https://preview.ncbi.nlm.nih.gov/clinvar/variation/194233/). We have observed this variant internally in several patients, generally without a second plausible causative variant in PYGM. In summary, although we suspect that this variant may possibly be benign, at this time its clinical significance is uncertain due to the absence of conclusive functional and genetic evidence.
GenomeConnect, ClinGen	RCV000509394	SCV000606998	not provided	Glycogen storage disease, type V		no assertion provided	phenotyping only	GenomeConnect assertions are reported exactly as they appear on the patient-provided report from the testing laboratory. GenomeConnect staff make no attempt to reinterpret the clinical significance of the variant.
Natera, Inc.	RCV000509394	SCV001452654	benign	Glycogen storage disease, type V	2020-01-12	no assertion criteria provided	clinical testing