ClinVar Miner

Submissions for variant NM_005609.4(PYGM):c.148C>T (p.Arg50Ter) (rs116987552)

Minimum review status: Collection method:
Minimum conflict level:
ClinVar version:
Total submissions: 20
Download table as spreadsheet
Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
EGL Genetic Diagnostics, Eurofins Clinical Diagnostics RCV000081306 SCV000077245 pathogenic not provided 2014-12-19 criteria provided, single submitter clinical testing
GeneDx RCV000081306 SCV000329478 pathogenic not provided 2018-10-23 criteria provided, single submitter clinical testing The R50Xnonsense variant is the most common pathogenic variant associated with glycogen storage diseasetype V in the Caucasian population and has been seen in the compound heterozygous state, as well asthe homozygous state (Tsujino et al., 1993; Deschauer et al., 2007; Gurgel-Giannetti et al., 2013).This variant is predicted to cause loss of normal protein function either through protein truncation ornonsense-mediated mRNA decay. A mouse model, homozygous for R50X, was found to haveundetectable myophosphorylase protein and enzyme activity in skeletal muscle as well as massivemuscle glycogen accumulation (Brull et al., 2015). Therefore, we interpret R50X to be a pathogenicvariant.
Illumina Clinical Services Laboratory,Illumina RCV000002388 SCV000373042 pathogenic Glycogen storage disease, type V 2017-04-27 criteria provided, single submitter clinical testing The PYGM c.148C>T (p.Arg50Ter) variant is a stop-gained variant that is predicted to result in a premature termination of the protein. The p.Arg50Ter variant is the most commonly identified variant in patients with glycogen storage disease type V, also known as McArdle disease, in the majority of populations studied (Martin et al. 2006; Nogales-Gadea et al. 2015). Across a selection of the available literature, the p.Arg50Ter variant is detected with an allele frequency ranging from 43%-78% in the respective patient cohorts (Tsujino et al. 1993; Bruno et al. 2006; Aquaron et al. 2007; Deschauer et al. 2007; Vieitez et al. 2011; Gurgel-Giannetti et al. 2013). The variant was absent from 96 healthy individuals but is reported at a frequency of 0.00314 in the European American population of the Exome Sequencing Project. A knock-in mouse model homozygous for the p.Arg50Ter variant displays a McArdle disease-like phenotype (Nogales-Gadea et al. 2012). Based on the collective evidence, the p.Arg50Ter 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.
Counsyl RCV000002388 SCV000485127 pathogenic Glycogen storage disease, type V 2016-03-08 criteria provided, single submitter clinical testing
Center for Pediatric Genomic Medicine,Children's Mercy Hospital and Clinics RCV000081306 SCV000511631 pathogenic not provided 2016-07-06 criteria provided, single submitter clinical testing
Molecular Diagnostics Lab,Nemours Alfred I. duPont Hospital for Children RCV000002388 SCV000590832 pathogenic Glycogen storage disease, type V 2016-01-12 criteria provided, single submitter clinical testing
Invitae RCV000002388 SCV000626780 pathogenic Glycogen storage disease, type V 2020-10-25 criteria provided, single submitter clinical testing This sequence change creates a premature translational stop signal (p.Arg50*) in the PYGM gene. It is expected to result in an absent or disrupted protein product. This variant is present in population databases (rs116987552, ExAC 0.2%). This particular variant is the most prevalent PYGM variant reported in individuals affected with McArdle disease, having been identified as homozygous in several cases (PMID: 8316268, 16786513, 21802952, 22250184, 23653251). ClinVar contains an entry for this variant (Variation ID: 2298). ClinVar contains an entry for this variant (Variation ID: 2298). Experimental studies have shown that this nonsense change causes a McArdle disease phenotype in knockin mice (PMID: 22730558). Loss-of-function variants in PYGM are known to be pathogenic (PMID: 8316268, 16786513). For these reasons, this variant has been classified as Pathogenic.
Laboratory for Molecular Medicine, Partners HealthCare Personalized Medicine RCV000002388 SCV000713109 pathogenic Glycogen storage disease, type V 2018-06-27 criteria provided, single submitter clinical testing The p.Arg50X variant in PYGM is a known pathogenic variant that has been report ed in at least 50 homozygotes and 29 compound heterozygous with glycogen storage disease type V (GSDV), also known as McArdle disease, and segregated with disea se in 5 affected siblings from 4 families (Tsujino 1993, Gurgel-Giannetti 2013, deLuna 2014, and Hongrel 2015). Mouse models demonstrate that this variant cause s glycogen storage disease type V (Nogales-Gadea 2012 and Brull 2015). It has al so been reported in ClinVar (Variation ID 2298) by multiple laboratories as path ogenic and has been identified in 0.20% (318/126684) of European chromosomes by gnomAD (http://gnomad.broadinstitute.org). This frequency is low enough to be co nsistent with a recessive carrier frequency. In summary, this variant meets crit eria to be classified as pathogenic for autosomal recessive GSDV based upon case observations, segregation studies, and animal models. ACMG/AMP Criteria applied : PVS1, PM3_Very Strong, PS3, PP1_Strong.
Ambry Genetics RCV000622729 SCV000740891 pathogenic Inborn genetic diseases 2014-09-07 criteria provided, single submitter clinical testing
Fulgent Genetics,Fulgent Genetics RCV000002388 SCV000893906 pathogenic Glycogen storage disease, type V 2018-10-31 criteria provided, single submitter clinical testing
CeGaT Praxis fuer Humangenetik Tuebingen RCV000081306 SCV001247785 pathogenic not provided 2020-12-01 criteria provided, single submitter clinical testing
Clinical Genetics Karolinska University Hospital,Karolinska University Hospital RCV000081306 SCV001449610 pathogenic not provided 2015-10-29 criteria provided, single submitter clinical testing
Mayo Clinic Laboratories, Mayo Clinic RCV000081306 SCV001714990 pathogenic not provided 2020-12-30 criteria provided, single submitter clinical testing PVS1, PS3, PP5
OMIM RCV000002388 SCV000022546 pathogenic Glycogen storage disease, type V 2007-07-01 no assertion criteria provided literature only
GeneReviews RCV000002388 SCV000172194 pathogenic Glycogen storage disease, type V 2014-06-26 no assertion criteria provided literature only
Natera, Inc. RCV000002388 SCV001454306 pathogenic Glycogen storage disease, type V 2020-09-16 no assertion criteria provided clinical testing
Department of Pathology and Laboratory Medicine,Sinai Health System RCV000081306 SCV001554240 pathogenic not provided no assertion criteria provided clinical testing The PYGM p.R50* variant is a well-known pathogenic variant known to cause McArdle disease and is the most common pathogenic variant in individuals of European and US descent (Martin_2019_PMID:20301518). The variant was identified in dbSNP (ID: rs116987552), ClinVar (classified as pathogenic by Counsyl, Ambry Genetics, GeneDx, EGL Genetic Diagnostics, Invitae, Laboratory for Molecular Medicine, Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics, Fulgent Genetics, Illumina and Molecular Diagnostics Lab, Nemours Alfred I. duPont Hospital for Children) and LOVD 3.0 (classified as pathogenic). The variant was identified in control databases in 424 of 282854 chromosomes at a frequency of 0.001499 (Genome Aggregation Database March 6, 2019, v2.1.1). The variant was observed in the following populations: European (non-Finnish) in 325 of 129154 chromosomes (freq: 0.002516), Other in 18 of 7226 chromosomes (freq: 0.002491), Latino in 48 of 35440 chromosomes (freq: 0.001354), African in 18 of 24972 chromosomes (freq: 0.000721), European (Finnish) in 12 of 25122 chromosomes (freq: 0.000478), Ashkenazi Jewish in 1 of 10370 chromosomes (freq: 0.000096), East Asian in 1 of 19954 chromosomes (freq: 0.00005), and South Asian in 1 of 30616 chromosomes (freq: 0.000033). The c.148C>T variant leads to a premature stop codon at position 50 which is predicted to lead to a truncated or absent protein and loss of function. Loss of function variants of the PYGM gene are an established mechanism of disease in McArdle disease and is the type of variant known to cause the disorder in the homozygous or compound heterozygous state. The variant occurs outside of the splicing consensus sequence and in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer) do not predict a difference in splicing. Mouse models with the p.R50* variant display a McArdle disease phenotype (Nogales-Gadea_2012_PMID:22730558; Brull_2015_PMID: 25873271). In summary, based on the above information this variant meets our laboratory’s criteria to be classified as pathogenic.
Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen RCV000081306 SCV001742786 pathogenic not provided no assertion criteria provided clinical testing
Genomics England Pilot Project,Genomics England RCV000002388 SCV001760270 likely pathogenic Glycogen storage disease, type V no assertion criteria provided clinical testing
Genome Diagnostics Laboratory, Amsterdam University Medical Center RCV000081306 SCV001807182 pathogenic not provided no assertion criteria provided clinical testing

The information on this website is not intended for direct diagnostic use or medical decision-making without review by a genetics professional. Individuals should not change their health behavior solely on the basis of information contained on this website. Neither the University of Utah nor the National Institutes of Health independently verfies the submitted information. If you have questions about the information contained on this website, please see a health care professional.