Submissions for variant NM_005609.4(PYGM):c.1094C>T (p.Ala365Val)

gnomAD frequency: 0.00074  dbSNP: rs116135678

Total submissions: 15

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Eurofins Ntd Llc (ga)	RCV000723508	SCV000331200	uncertain significance	not provided	2015-10-26	criteria provided, single submitter	clinical testing
Illumina Laboratory Services, Illumina	RCV000185576	SCV000373025	likely pathogenic	Glycogen storage disease, type V	2017-04-27	criteria provided, single submitter	clinical testing	The PYGM c.1094C>T (p.Arg365Val) missense variant has been reported in four studies in which it is found in a compound heterozygous state in five patients with glycogen storage disease type V, and in two additional patient alleles of unknown zygosity (Bruno et al. 2006; Rubio et al. 2007; Rubio et al. 2007; Lucia et al. 2012). The p.Arg365Val variant was absent from 246 controls but is reported at a frequency of 0.00851 in the other population of the Exome Aggregation Consortium. The Arg365 variant is located in a highly conserved region of the protein (Rubio et al. 2007). Based on the evidence the p.Arg365Val variant is classified as likely pathogenic for glycogen storage disease type V. This variant was observed by ICSL as part of a predisposition screen in an ostensibly healthy population.
Labcorp Genetics (formerly Invitae), Labcorp	RCV000185576	SCV000830856	uncertain significance	Glycogen storage disease, type V	2022-11-01	criteria provided, single submitter	clinical testing	This sequence change replaces alanine, which is neutral and non-polar, with valine, which is neutral and non-polar, at codon 365 of the PYGM protein (p.Ala365Val). This variant is present in population databases (rs116135678, gnomAD 0.1%), 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: 17221871, 29143597; Invitae). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. ClinVar contains an entry for this variant (Variation ID: 203394). Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Not Available"; PolyPhen-2: "Possibly Damaging"; Align-GVGD: "Not Available"). 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	RCV000723508	SCV001247784	uncertain significance	not provided	2024-02-01	criteria provided, single submitter	clinical testing	PYGM: PM2, PM3
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000185576	SCV001519532	pathogenic	Glycogen storage disease, type V	2024-08-27	criteria provided, single submitter	clinical testing	Variant summary: PYGM c.1094C>T (p.Ala365Val) 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. Several computational tools predict a significant impact on normal splicing: Three predict the variant creates a 5 donor site. One predict the variant strengthens a 5 donor site. However, these predictions have yet to be confirmed by functional studies. The variant allele was found at a frequency of 0.00071 in 224920 control chromosomes. This frequency is not significantly higher than estimated for a pathogenic variant in PYGM causing Glycogen Storage Disease, Type V (0.00071 vs 0.0035), allowing no conclusion about variant significance. c.1094C>T has been reported in the literature in multiple compound heterozygous individuals affected with Glycogen Storage Disease, Type V (Vieitez_2011, Rubio_2007, Bruno_2006, Lucia_2012, Inal-Gultekin_2017, Santalla_2017, Lkken_2023). These data indicate that the variant is very likely to be associated with disease. 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: 25741863, 16786513, 28967462, 37769369, 22250184, 17221871, 29143597, 21802952). ClinVar contains an entry for this variant (Variation ID: 203394). Based on the evidence outlined above, the variant was classified as pathogenic.
Mayo Clinic Laboratories, Mayo Clinic	RCV000723508	SCV001714985	likely pathogenic	not provided	2020-02-10	criteria provided, single submitter	clinical testing	PS4_moderate, PM2, PP3, PP4
Genome-Nilou Lab	RCV000185576	SCV001737323	uncertain significance	Glycogen storage disease, type V	2021-06-10	criteria provided, single submitter	clinical testing
GeneDx	RCV000723508	SCV001987417	likely pathogenic	not provided	2022-04-26	criteria provided, single submitter	clinical testing	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: 21802952, 20981092, 16786513, 17221871, 17630210, 29143597, 22250184, 34426522, 25741863, 29907799, 28967462, 30011114)
Practice for Gait Abnormalities, David Pomarino, Competency Network Toe Walking c/o Practice Pomarino	RCV001822854	SCV002072497	pathogenic	Tip-toe gait	2022-01-11	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.
Revvity Omics, Revvity	RCV000185576	SCV003810370	uncertain significance	Glycogen storage disease, type V	2023-11-08	criteria provided, single submitter	clinical testing
Baylor Genetics	RCV000185576	SCV004207203	pathogenic	Glycogen storage disease, type V	2024-03-30	criteria provided, single submitter	clinical testing
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	RCV000185576	SCV004848716	likely pathogenic	Glycogen storage disease, type V	2022-06-30	criteria provided, single submitter	clinical testing	The p.Ala365Val variant in PYGM has been reported, in the compound heterozygous state, in over 5 individuals with Glycogen Storage Disease, Type V (McArdle disease ) (Vieitez 2011 PMID: 21802952, Rubio 2007 PMID: 17630210, Bruno 2006 PMID: 16786513, Lucia 2012 PMID: 22250184, Inal-Gultekin 2017 PMID: 28967462, Santalla 2017 PMID: 29143597). This variant has been reported in ClinVar (Variation ID 203394) and it has been identified in 71/68026 European chromosomes by gnomAD (https://gnomad.broadinstitute.org/). Computational prediction tools and conservation analyses suggest that this variant may impact the protein, though this information is not predictive enough to determine pathogenicity. In summary, although additional studies are required to fully establish its clinical significance, this variant meets criteria to be classified as likely pathogenic for autosomal recessive Glycogen Storage Disease, Type V. ACMG/AMP Criteria applied: PM3_Very Strong, PP3.
Division of Human Genetics, Children's Hospital of Philadelphia	RCV000185576	SCV000238476	likely pathogenic	Glycogen storage disease, type V	2015-05-27	no assertion criteria provided	research	The variant (c.1094C>T; p.A365V) is considered to be likely pathogenic because it has been reported in several patients with biochemically proven McArdle disease across multiple cohorts and has been modeled to occur in a very densely packed and critical region of the gene for glycogen binding (PMID: 21802952; 17630210; 17221871). It occurs at low frequencies in ExAC (allele frequency of 65 out of 62854 alleles, 0.1%). The variant occurs in highly conserved amino acid and nucleotide positions but not in a functional domain.
Natera, Inc.	RCV000185576	SCV001461285	uncertain significance	Glycogen storage disease, type V	2020-09-16	no assertion criteria provided	clinical testing
Department of Pathology and Laboratory Medicine, Sinai Health System	RCV000723508	SCV001552232	uncertain significance	not provided		no assertion criteria provided	clinical testing	The PYGM p.Ala277Val variant was identified in 5 of 666 proband chromosomes (frequency: 0.0075) from individuals with McArdle disease (Santalla_2017_PMID:29143597). The variant was identified in dbSNP (ID: rs116135678) and ClinVar (classified as uncertain significance by Invitae and EGL Genetics and as likely pathogenic by Illumina and Division of Human Genetics, Children's Hospital of Philadelphia). The variant was also identified in control databases in 172 of 256272 chromosomes at a frequency of 0.0006712 increasing the likelihood this could be a low frequency benign variant (Genome Aggregation Database March 6, 2019, v2.1.1). The variant was observed in the following populations: Ashkenazi Jewish in 10 of 9824 chromosomes (freq: 0.001018), European (non-Finnish) in 115 of 115330 chromosomes (freq: 0.000997), Latino in 30 of 32778 chromosomes (freq: 0.000915), Other in 6 of 6708 chromosomes (freq: 0.000895), African in 5 of 22454 chromosomes (freq: 0.000223), South Asian in 4 of 28262 chromosomes (freq: 0.000142), East Asian in 1 of 18386 chromosomes (freq: 0.000054), and European (Finnish) in 1 of 22530 chromosomes (freq: 0.000044). The p.Ala277 residue is not conserved in mammals and computational analyses (PolyPhen-2, SIFT, AlignGVGD, BLOSUM, MutationTaster) provide inconsistent predictions regarding the impact to the protein; this information is not very predictive of pathogenicity. The variant occurs outside of the splicing consensus sequence however three of four in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer) predict a greater than 10% difference in splicing. In summary, based on the above information the clinical significance of this variant cannot be determined with certainty at this time. This variant is classified as a variant of uncertain significance.