ClinVar Miner

Submissions for variant NM_000540.3(RYR1):c.1198G>A (p.Ala400Thr)

dbSNP: rs777016690
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Total submissions: 5
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
PreventionGenetics, part of Exact Sciences RCV000721257 SCV000852277 uncertain significance not provided 2016-07-18 criteria provided, single submitter clinical testing
Labcorp Genetics (formerly Invitae), Labcorp RCV000820328 SCV000961036 pathogenic RYR1-related disorder 2024-01-31 criteria provided, single submitter clinical testing This sequence change replaces alanine, which is neutral and non-polar, with threonine, which is neutral and polar, at codon 400 of the RYR1 protein (p.Ala400Thr). This variant is present in population databases (rs777016690, gnomAD 0.003%). This missense change has been observed in individual(s) with clinical features of autosomal recessive RYR1-related myopathy and/or myopathy (PMID: 1069529; Invitae). 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: 590393). 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) has been performed at Invitae for this missense variant, however the output from this modeling did not meet the statistical confidence thresholds required to predict the impact of this variant on RYR1 protein function. For these reasons, this variant has been classified as Pathogenic.
GeneDx RCV000721257 SCV002549243 likely pathogenic not provided 2023-01-17 criteria provided, single submitter clinical testing Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Identified in a patient with myopathy in published literature (PMID: 31069529); This variant is associated with the following publications: (PMID: 31069529)
All of Us Research Program, National Institutes of Health RCV004807114 SCV005430475 uncertain significance Malignant hyperthermia, susceptibility to, 1 2024-02-22 criteria provided, single submitter clinical testing This missense variant replaces alanine with threonine at codon 400 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). 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: 590393). This variant has been identified in 1/251420 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.
Fulgent Genetics, Fulgent Genetics RCV005027887 SCV005647451 likely pathogenic Central core myopathy; Malignant hyperthermia, susceptibility to, 1; Congenital multicore myopathy with external ophthalmoplegia; King Denborough syndrome 2024-05-29 criteria provided, single submitter clinical testing

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