ClinVar Miner

Submissions for variant NM_000540.3(RYR1):c.9742C>T (p.Arg3248Trp)

gnomAD frequency: 0.00001  dbSNP: rs761656403
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Total submissions: 3
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Labcorp Genetics (formerly Invitae), Labcorp RCV001350902 SCV001545330 uncertain significance RYR1-related disorder 2023-10-17 criteria provided, single submitter clinical testing This sequence change replaces arginine, which is basic and polar, with tryptophan, which is neutral and slightly polar, at codon 3248 of the RYR1 protein (p.Arg3248Trp). This variant is present in population databases (rs761656403, gnomAD 0.01%). This missense change has been observed in individual(s) with malignant hyperthermia susceptibility (Invitae). ClinVar contains an entry for this variant (Variation ID: 1046349). 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.
All of Us Research Program, National Institutes of Health RCV004005236 SCV004829170 uncertain significance Malignant hyperthermia, susceptibility to, 1 2023-12-01 criteria provided, single submitter clinical testing This missense variant replaces arginine with tryptophan at codon 3248 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 4/249350 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.
Ambry Genetics RCV004960847 SCV005496937 uncertain significance Inborn genetic diseases 2024-12-07 criteria provided, single submitter clinical testing The c.9742C>T (p.R3248W) alteration is located in exon 66 (coding exon 66) of the RYR1 gene. This alteration results from a C to T substitution at nucleotide position 9742, causing the arginine (R) at amino acid position 3248 to be replaced by a tryptophan (W). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear.

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