ClinVar Miner

Submissions for variant NM_000540.3(RYR1):c.6359T>C (p.Met2120Thr)

gnomAD frequency: 0.00002  dbSNP: rs398123473
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Total submissions: 5
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Eurofins Ntd Llc (ga) RCV000079157 SCV000111026 uncertain significance not provided 2012-08-20 criteria provided, single submitter clinical testing
Fulgent Genetics, Fulgent Genetics RCV002490686 SCV002785826 uncertain significance Central core myopathy; Malignant hyperthermia, susceptibility to, 1; Congenital multicore myopathy with external ophthalmoplegia; Congenital myopathy with fiber type disproportion; King Denborough syndrome 2021-09-22 criteria provided, single submitter clinical testing
Invitae RCV002515759 SCV003473368 likely pathogenic RYR1-related disorder 2024-01-31 criteria provided, single submitter clinical testing This sequence change replaces methionine, which is neutral and non-polar, with threonine, which is neutral and polar, at codon 2120 of the RYR1 protein (p.Met2120Thr). This variant is present in population databases (rs398123473, gnomAD 0.01%). This missense change has been observed in individual(s) with clinical features of autosomal recessive RYR1-related conditions (PMID: 30611313). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. ClinVar contains an entry for this variant (Variation ID: 93280). 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 with a positive predictive value of 95%. In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic.
Revvity Omics, Revvity RCV000079157 SCV003810564 uncertain significance not provided 2022-05-23 criteria provided, single submitter clinical testing
All of Us Research Program, National Institutes of Health RCV003997199 SCV004839509 uncertain significance Malignant hyperthermia, susceptibility to, 1 2023-11-02 criteria provided, single submitter clinical testing This missense variant replaces methionine with threonine at codon 2120 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). This variant occurs in a region of the RYR1 protein that is considered to be a hotspot for pathogenic variants that contribute to malignant hyperthermia susceptibility (PMID: 21118704). To our knowledge, functional studies have not been reported for this variant. This variant has not been reported in individuals affected with autosomal dominant malignant hyperthermia in the literature, although it is associated with other phenotype(s) (ClinVar variation ID: 93280). This variant has been identified in 3/250306 chromosomes in the general population by the Genome Aggregation Database (gnomAD). Due to insufficient evidence, this variant is classified as a Variant of Uncertain Significance for autosomal dominant malignant hyperthermia.

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