ClinVar Miner

Submissions for variant NM_000540.3(RYR1):c.658C>T (p.Arg220Cys)

gnomAD frequency: 0.00001  dbSNP: rs1220780685
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Total submissions: 3
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Pediatric Department, Peking University First Hospital RCV001260945 SCV001245550 likely pathogenic Congenital multicore myopathy with external ophthalmoplegia 2020-04-11 criteria provided, single submitter provider interpretation
Labcorp Genetics (formerly Invitae), Labcorp RCV002555937 SCV003443293 uncertain significance RYR1-related disorder 2022-09-07 criteria provided, single submitter clinical testing This sequence change replaces arginine, which is basic and polar, with cysteine, which is neutral and slightly polar, at codon 220 of the RYR1 protein (p.Arg220Cys). This variant is present in population databases (no rsID available, gnomAD 0.01%). This missense change has been observed in individual(s) with autosomal recessive RYR1-related conditions (PMID: 27353517). ClinVar contains an entry for this variant (Variation ID: 870622). 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. 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.
All of Us Research Program, National Institutes of Health RCV004807305 SCV005430454 uncertain significance Malignant hyperthermia, susceptibility to, 1 2024-05-14 criteria provided, single submitter clinical testing This missense variant replaces arginine with cysteine at codon 220 of the RYR1 protein. Computational prediction tools are inconclusive regarding the role of this variant in RYR1 protein structure and function. To our knowledge, functional studies have not been reported for this variant. This variant has not been reported in individuals affected with malignant hyperthermia susceptibility in the literature but has been observed in individuals with congenital myopathy (ClinVar variation ID: 870622). This variant has been identified in 2/251470 chromosomes in the general population by the Genome Aggregation Database (gnomAD). The available evidence is insufficient to determine the role of this variant in autosomal dominant malignant hyperthermia susceptibility conclusively. Therefore, this variant is classified as a Variant of Uncertain Significance.

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