ClinVar

Description

The heterozygous p.Ile4898Thr variant in RYR1 was identified by our study in 1 individual with congenital myopathy. The p.Ile4898Thr variant in RYR1 has been reported in at least 7 families with congenital myopathy, segregated with disease in 26 affected relatives from 2 families (PMID: 10097181, PMID: 11741831), and has been identified in 0.00008% (1/1179980) of European (non-Finnish) chromosomes by the Genome Aggregation Database (gnomAD, http://gnomad.broadinstitute.org; dbSNP ID: rs118192170). 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: 12975) and has been interpreted as pathogenic by multiple submitters for congenital myopathy, and as a variant of uncertain significance by the ClinGen Malignant Hyperthermia Susceptibility Variant Curation Expert Panel. This variant was found to be de novo in monozygotic twins with confirmed paternity and maternity (PMID: 20888934). The number of reported affected individuals with this variant is greater than expected compared to non-affected individuals with this variant. In vitro functional studies provide some evidence that the p.Ile4898Thr variant may slightly impact protein function (PMID: 10097181, 11741831). However, these types of assays may not accurately represent biological function. Computational prediction tools and conservation analyses suggest that this variant may impact the protein, though this information is not predictive enough to determine pathogenicity. The number of missense variants reported in RYR1 in the general population is lower than expected, suggesting there is little benign variation in this gene and slightly increasing the possibility that a missense variant in this gene may not be tolerated. In summary, this variant meets criteria to be classified as pathogenic for autosomal dominant congenital myopathy. ACMG/AMP Criteria applied: PP1_strong, PP3_moderate, PS4_moderate, PP2, PM2_supporting PS2_supporting, PS3_supporting (Richards 2015).