ClinVar Miner

Submissions for variant NM_000540.3(RYR1):c.5086G>A (p.Ala1696Thr)

gnomAD frequency: 0.00002  dbSNP: rs1179510850
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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 RCV000721578 SCV000852670 uncertain significance not provided 2016-08-19 criteria provided, single submitter clinical testing
GeneDx RCV000721578 SCV001796892 uncertain significance not provided 2024-05-28 criteria provided, single submitter clinical testing Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect; Reported as being present in an individual with presumed RYR1-related myopathy (PMID: 32236737); This variant is associated with the following publications: (PMID: 32236737)
Labcorp Genetics (formerly Invitae), Labcorp RCV001862099 SCV002179832 uncertain significance RYR1-related disorder 2021-09-08 criteria provided, single submitter clinical testing This sequence change replaces alanine with threonine at codon 1696 of the RYR1 protein (p.Ala1696Thr). The alanine residue is moderately conserved and there is a small physicochemical difference between alanine and threonine. This variant is not present in population databases (ExAC no frequency). This variant has not been reported in the literature in individuals affected with RYR1-related conditions. ClinVar contains an entry for this variant (Variation ID: 590551). 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 not 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.
Revvity Omics, Revvity RCV000721578 SCV003812496 uncertain significance not provided 2022-12-13 criteria provided, single submitter clinical testing
All of Us Research Program, National Institutes of Health RCV003999849 SCV004815216 uncertain significance Malignant hyperthermia, susceptibility to, 1 2024-07-20 criteria provided, single submitter clinical testing This missense variant replaces alanine with threonine at codon 1696 of the RYR1 protein. Computational prediction suggests that this variant may not impact protein structure and function (internally defined REVEL score threshold <= 0.5, PMID: 27666373). To our knowledge, functional studies have not been reported for this variant. This variant has not been reported in individuals affected with RYR1-related disorders in the literature. This variant has been identified in 4/247244 chromosomes 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.

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