ClinVar

Description

The heterozygous p.Arg2542Gln variant in RYR1 was identified by our study in one individual with congenital myopathy. The p.Arg2542Gln variant in RYR1 has been previously reported in one individual with RYR1-related disease (PMID: 16917943) but has been identified in 0.001% (1/113550) of European (non-Finnish) chromosomes by the Genome Aggregation Database (gnomAD, http://gnomad.broadinstitute.org; dbSNP ID: rs193922815). Although this variant has been seen in the general population in a heterozygous state, its frequency is not high enough to rule out a pathogenic role. This variant has also been reported in ClinVar (Variation ID:133201) and has been interpreted as pathogenic by CeGaT Center for Human Genetics Tuebingen and as a variant of uncertain significance by the ClinGen Malignant Hyperthermia Susceptibility Variant Curation Expert Panel and Invitae. Computational prediction tools and conservation analyses suggest that this variant may impact the protein, though this information is not predictive enough to determine pathogenicity. Multiple variants in the same region as the p.Arg2542Gln variant have been reported in association with disease in the literature, suggesting that this variant is in a hot spot and slightly supports pathogenicity (PMID: 21118704). One additional likely pathogenic variant, resulting in a different amino acid change at the same position, p.Arg2452Trp, has been reported in association with disease in ClinVar, slightly supporting that a change at this position may not be tolerated (ClinVar Variation ID: 65979). In summary, the clinical significance of the p.Arg2542Gln variant is uncertain. ACMG/AMP Criteria applied: PM1_Supporting, PM5_Supporting, PP3 (Richards 2015).