ClinVar Miner

Submissions for variant NM_000540.3(RYR1):c.10282A>G (p.Asn3428Asp)

gnomAD frequency: 0.00002  dbSNP: rs763976533
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Total submissions: 4
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Labcorp Genetics (formerly Invitae), Labcorp RCV000688758 SCV000816382 uncertain significance RYR1-related disorder 2021-08-27 criteria provided, single submitter clinical testing This sequence change replaces asparagine with aspartic acid at codon 3428 of the RYR1 protein (p.Asn3428Asp). The asparagine residue is moderately conserved and there is a small physicochemical difference between asparagine and aspartic acid. This variant is present in population databases (rs763976533, ExAC 0.003%). This variant has not been reported in the literature in individuals affected with RYR1-related conditions. Algorithms developed to predict the effect of missense changes on protein structure and function output the following: SIFT: "Tolerated"; PolyPhen-2: "Benign"; Align-GVGD: "Class C0". The aspartic acid amino acid residue is found in multiple mammalian species, which suggests that this missense change does not adversely affect 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.
GeneDx RCV001771941 SCV001993847 uncertain significance not provided 2019-05-09 criteria provided, single submitter clinical testing Has not been previously published as pathogenic or benign to our knowledge; Not observed at a significant frequency in large population cohorts (Lek et al., 2016); In silico analysis, which includes protein predictors and evolutionary conservation, supports that this variant does not alter protein structure/function
Fulgent Genetics, Fulgent Genetics RCV002477539 SCV002800148 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 2021-09-07 criteria provided, single submitter clinical testing
All of Us Research Program, National Institutes of Health RCV004004286 SCV004819649 uncertain significance Malignant hyperthermia, susceptibility to, 1 2023-12-18 criteria provided, single submitter clinical testing This missense variant replaces asparagine with aspartic acid at codon 3428 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 5/271200 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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