ClinVar Miner

Submissions for variant NM_000540.3(RYR1):c.10505G>A (p.Arg3502Gln)

gnomAD frequency: 0.00004  dbSNP: rs369422480
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Total submissions: 6
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
PreventionGenetics, part of Exact Sciences RCV000721203 SCV000852213 uncertain significance not provided 2015-09-18 criteria provided, single submitter clinical testing
CeGaT Center for Human Genetics Tuebingen RCV000721203 SCV000892254 uncertain significance not provided 2018-09-30 criteria provided, single submitter clinical testing
Fulgent Genetics, Fulgent Genetics RCV002485815 SCV002780768 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 2021-10-12 criteria provided, single submitter clinical testing
Labcorp Genetics (formerly Invitae), Labcorp RCV002533060 SCV003032631 uncertain significance RYR1-related disorder 2024-01-24 criteria provided, single submitter clinical testing This sequence change replaces arginine, which is basic and polar, with glutamine, which is neutral and polar, at codon 3502 of the RYR1 protein (p.Arg3502Gln). This variant is present in population databases (rs369422480, gnomAD 0.004%). 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: 590368). 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) has been performed at Invitae for this missense variant, however the output from this modeling did not meet the statistical confidence thresholds required to predict the impact of this variant on 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.
Revvity Omics, Revvity RCV000721203 SCV003812446 uncertain significance not provided 2021-08-09 criteria provided, single submitter clinical testing
All of Us Research Program, National Institutes of Health RCV003999807 SCV004827540 uncertain significance Malignant hyperthermia, susceptibility to, 1 2023-12-13 criteria provided, single submitter clinical testing This missense variant replaces arginine with glutamine at codon 3502 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 7/282630 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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