ClinVar Miner

Submissions for variant NM_000540.3(RYR1):c.4415C>T (p.Thr1472Met)

gnomAD frequency: 0.00003  dbSNP: rs1318296270
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Total submissions: 5
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Invitae RCV000823036 SCV000963874 uncertain significance RYR1-related disorder 2021-08-27 criteria provided, single submitter clinical testing This sequence change replaces threonine with methionine at codon 1472 of the RYR1 protein (p.Thr1472Met). The threonine residue is highly conserved and there is a moderate physicochemical difference between threonine and methionine. 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. Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Probably Damaging"; Align-GVGD: "Class C0"). 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.
GeneDx RCV001577014 SCV001804322 uncertain significance not provided 2021-05-12 criteria provided, single submitter clinical testing Not observed at a significant frequency in large population cohorts (Lek et al., 2016); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Has not been previously published as pathogenic or benign to our knowledge
Fulgent Genetics, Fulgent Genetics RCV002478927 SCV002797685 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 2021-08-27 criteria provided, single submitter clinical testing
PreventionGenetics, part of Exact Sciences RCV000823036 SCV004104597 uncertain significance RYR1-related disorder 2023-08-14 criteria provided, single submitter clinical testing The RYR1 c.4415C>T variant is predicted to result in the amino acid substitution p.Thr1472Met. To our knowledge, this variant has not been reported in the literature. This variant is reported in 0.0058% of alleles in individuals of Latino descent in gnomAD (http://gnomad.broadinstitute.org/variant/19-38968471-C-T). At this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence.
All of Us Research Program, National Institutes of Health RCV004002851 SCV004831161 uncertain significance Malignant hyperthermia, susceptibility to, 1 2023-08-15 criteria provided, single submitter clinical testing This missense variant replaces threonine with methionine at codon 1472 of the RYR1 protein. Computational prediction is inconclusive regarding the impact of this variant on protein structure and function (internally defined REVEL score threshold 0.5 < inconclusive < 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 RYR1-related disorders in the literature. This variant has been identified in 4/251028 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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