Total submissions: 3
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| Gene |
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 | |
| Invitae | RCV000675078 | SCV003517633 | uncertain significance | Glycogen storage disease, type V | 2022-10-17 | criteria provided, single submitter | clinical testing | This sequence change replaces proline, which is neutral and non-polar, with serine, which is neutral and polar, at codon 489 of the PYGM protein (p.Pro489Ser). This variant is present in population databases (rs752622662, gnomAD 0.006%). This variant has not been reported in the literature in individuals affected with PYGM-related conditions. ClinVar contains an entry for this variant (Variation ID: 424518). 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) has been performed at Invitae for this missense variant, however the output from this modeling did not meet the statistical confidence thresholds required to predict the impact of this variant on 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. |