ClinVar Miner

Submissions for variant NM_000540.3(RYR1):c.3044G>A (p.Arg1015His)

gnomAD frequency: 0.00001  dbSNP: rs1202647394
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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 RCV001040534 SCV001204114 uncertain significance RYR1-related disorder 2022-08-22 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 1015 of the RYR1 protein (p.Arg1015His). The frequency data for this variant in the population databases is considered unreliable, as metrics indicate poor data quality at this position in the gnomAD database. 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: 838886). 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 RCV004004733 SCV004834288 uncertain significance Malignant hyperthermia, susceptibility to, 1 2023-12-13 criteria provided, single submitter clinical testing This missense variant replaces arginine with histidine at codon 1015 of the RYR1 protein. Computational prediction suggests that this variant may not impact protein structure and function (internally defined REVEL score threshold <= 0.6, 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 2/247570 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.
GeneDx RCV004721721 SCV005326765 uncertain significance not provided 2024-03-13 criteria provided, single submitter clinical testing Reported as a de novo variant in an individual from a large cohort study of autism spectrum disorder; no further clinical details were provided (PMID: 28714951); Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 35982160, 35982159, 28714951)

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