ClinVar Miner

Submissions for variant NM_005609.4(PYGM):c.808C>T (p.Arg270Ter) (rs767739769)

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Total submissions: 4
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Counsyl RCV000169167 SCV000220397 likely pathogenic Glycogen storage disease, type V 2014-06-10 criteria provided, single submitter literature only
GeneDx RCV000627209 SCV000748196 pathogenic not provided 2018-02-12 criteria provided, single submitter clinical testing The R270X nonsense variant in the PYGM gene has been reported previously in a patient of Italian origin with McArdle disease (Glycogen Storage Disease type V (GSD V)) (Deschauer, M et al., 2001). The reported patient was homozygous for this pathogenic variant. This variant is predicted to cause loss of normal protein function either through protein truncation or nonsense-mediated mRNA decay. The R50X pathogenic variant in the PYGM gene is the most common variant associated with GSD V in the Caucasian population (Deschauer et al., 2007). This variant is also predicted to cause loss of normal protein function either through protein truncation or nonsense-mediated mRNA decay.
Invitae RCV000169167 SCV000827917 pathogenic Glycogen storage disease, type V 2018-04-24 criteria provided, single submitter clinical testing This sequence change creates a premature translational stop signal (p.Arg270*) in the PYGM gene. It is expected to result in an absent or disrupted protein product. This variant is present in population databases (rs767739769, ExAC 0.003%). This variant has been reported as homozygous or in combination with other pathogenic variants in the PYGM gene in several individuals affected with McArdle disease (PMID: 11749054, 12031624, 14748827, 16786513, 17404776, 19472443). This variant is also known as R269X in the literature. ClinVar contains an entry for this variant (Variation ID: 188824). 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 RCV000169167 SCV000966858 likely pathogenic Glycogen storage disease, type V 2018-07-05 criteria provided, single submitter clinical testing The p.Arg270X variant in PYGM has been previously reported in 1 homozygous indiv idual with McArdle disease (Deshauer, 2001) and in ClinVar (Variation ID#188824) . This variant has also been identified in 0.005% (6/11690) of European chromoso mes by the Genome Aggregation Database (gnomAD, http://gnomad.broadinstitute.org ). Although this variant has been seen in the general population, its frequency is low enough to be consistent with a recessive carrier frequency. This nonsense variant leads to a premature termination codon at position 270, which is predic ted to lead to a truncated or absent protein. Biallelic loss of function of the PYGM gene is an established disease mechanism in McArdle disease (glycogen stora ge disease type V). In summary, although additional studies are required to full y establish its clinical significance, the p.Arg270X variant is likely pathogeni c. ACMG/AMP Criteria applied: PVS1, PM2.

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