ClinVar Miner

Submissions for variant NM_000540.3(RYR1):c.13465C>T (p.Pro4489Ser)

gnomAD frequency: 0.00004  dbSNP: rs781766697
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Total submissions: 5
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Labcorp Genetics (formerly Invitae), Labcorp RCV001239624 SCV001412510 uncertain significance RYR1-related disorder 2023-12-14 criteria provided, single submitter clinical testing This sequence change replaces proline, which is neutral and non-polar, with serine, which is neutral and polar, at codon 4489 of the RYR1 protein (p.Pro4489Ser). This variant is present in population databases (rs781766697, gnomAD 0.005%). 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: 965229). 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 with a negative predictive value of 95%. 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 RCV002276668 SCV002567589 uncertain significance not provided 2022-02-17 criteria provided, single submitter clinical testing Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant does not alter protein structure/function; Has not been previously published as pathogenic or benign to our knowledge
Fulgent Genetics, Fulgent Genetics RCV002504340 SCV002815466 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 2021-11-08 criteria provided, single submitter clinical testing
Revvity Omics, Revvity RCV002276668 SCV003812421 uncertain significance not provided 2020-10-14 criteria provided, single submitter clinical testing
All of Us Research Program, National Institutes of Health RCV004004879 SCV004816234 uncertain significance Malignant hyperthermia, susceptibility to, 1 2024-09-23 criteria provided, single submitter clinical testing This missense variant replaces proline with serine at codon 4489 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 8/266186 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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