ClinVar Genomic variation as it relates to human health

For these reasons, this variant has been classified as Pathogenic. This variant disrupts the p.Arg4825 amino acid residue in RYR1. Other variant(s) that disrupt this residue have been observed in individuals with RYR1-related conditions (PMID: 16917943), which suggests that this may be a clinically significant amino acid residue. 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) performed at Invitae indicates that this missense variant is expected to disrupt RYR1 protein function. ClinVar contains an entry for this variant (Variation ID: 65985). This missense change has been observed in individual(s) with autosomal dominant malignant hyperthermia and/or central core disease and clinical features of autosomal recessive RYR1-related conditions (PMID: 11709545, 17204937, 35081925, 35428369). It has also been observed to segregate with disease in related individuals. This variant is not present in population databases (gnomAD no frequency). This sequence change replaces arginine, which is basic and polar, with cysteine, which is neutral and slightly polar, at codon 4825 of the RYR1 protein (p.Arg4825Cys).

The RYR1 c.14473C>T (p.Arg4825Cys) has been reported in at least two individuals affected with central core disease and/or malignant hyperthermia and segregated with disease in at least two individuals in one family (Herasse M et al., PMID: 17204937; Monnier N et al., PMID: 11709545). Another variant in the same codon, c.14474G>C (p.Arg4825Pro), has been reported in affected individuals (Robinson R et al., PMID: 16917943). This variant has been reported in the ClinVar database as a germline pathogenic variant for RYR-related disorders by one submitter. Based on available information and the ACMG/AMP guidelines for variant interpretation (Richards S et al., PMID: 25741868), this variant is classified as likely pathogenic.

This missense variant replaces arginine with cysteine at codon 4825 of the RYR1 protein. Computational prediction suggests that this variant may have deleterious impact on protein structure and function (internally defined REVEL score threshold >= 0.7, PMID: 27666373). Although functional studies have not been reported for this variant, it occurs in a region of RYR1 considered to be a hotspot for pathogenic variants that contribute to malignant hyperthermia susceptibility (PMID: 21118704). This variant has not been reported in individuals affected with malignant hyperthermia in the literature. This variant has not been identified in the general population by the Genome Aggregation Database (gnomAD). The available evidence is insufficient to determine the role of this variant in disease conclusively. Therefore, this variant is classified as a Variant of Uncertain Significance.

Converted during submission to Pathogenic.