ClinVar Miner

Submissions for variant NM_005609.4(PYGM):c.1465C>T (p.Pro489Ser) (rs752622662)

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Total submissions: 2
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000480329 SCV000574335 likely pathogenic not provided 2017-03-27 criteria provided, single submitter clinical testing A variant that is likely pathogenic has been identified in the PYGM gene. The P489S variant has not been published as a pathogenic variant, nor has it been reported as a benign variant to our knowledge. However, a different missense variant at the same position (P489R) has been reported previously in an individual with McArdle disease who also had a second pathogenic PYGM variant identified (Duno et al., 2009). The P489S variant is not observed at a significant frequency in large population cohorts (Lek et al., 2016; 1000 Genomes Consortium et al., 2015; Exome Variant Server). The P489S variant is a non-conservative amino acid substitution, which is likely to impact secondary protein structure as these residues differ in polarity, charge, size and/or other properties. This substitution occurs at a position that is conserved across species, and multiple missense variants in nearby residues have been reported in the Human Gene Mutation Database in association with McArdle disease (Stenson et al., 2014), supporting the functional importance of this region of the protein. In silico analysis predicts this variant is probably damaging to the protein structure/function. Therefore, this variant is likely pathogenic; however, the possibility that it is benign cannot be excluded.
Counsyl RCV000675078 SCV000800576 uncertain significance Glycogen storage disease, type V 2017-08-16 criteria provided, single submitter clinical testing

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