ClinVar Miner

Submissions for variant NM_000540.3(RYR1):c.12560G>A (p.Arg4187His)

gnomAD frequency: 0.00006  dbSNP: rs767099429
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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 RCV000798180 SCV000937782 uncertain significance RYR1-related disorder 2024-12-08 criteria provided, single submitter clinical testing This sequence change replaces arginine, which is basic and polar, with histidine, which is basic and polar, at codon 4187 of the RYR1 protein (p.Arg4187His). This variant is present in population databases (rs767099429, gnomAD 0.02%). 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: 644294). Invitae Evidence Modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) indicates that this missense variant is not expected to disrupt RYR1 protein function with a negative predictive value of 80%. 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.
Fulgent Genetics, Fulgent Genetics RCV002487677 SCV002782040 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 2021-08-10 criteria provided, single submitter clinical testing
All of Us Research Program, National Institutes of Health RCV004001616 SCV004816226 uncertain significance Malignant hyperthermia, susceptibility to, 1 2023-11-20 criteria provided, single submitter clinical testing This missense variant replaces arginine with histidine at codon 4187 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 malignant hyperthermia in the literature. This variant has been identified in 5/280844 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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