ClinVar Miner

Submissions for variant NM_000540.3(RYR1):c.12608A>G (p.Gln4203Arg)

gnomAD frequency: 0.00001  dbSNP: rs757438220
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Total submissions: 5
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000494306 SCV000582167 uncertain significance not provided 2017-05-11 criteria provided, single submitter clinical testing The Q4203R variant in the RYR1 gene has not been reported previously as a pathogenic variant, nor as a benign variant, to our knowledge. The Q4203R variant is not observed at a significant frequency in large population cohorts (Lek et al., 2016; 1000 Genomes Consortium et al., 2015; Exome Variant Server). The Q4203R variant is a semi-conservative amino acid substitution, which may impact secondary protein structure as these residues differ in some properties. This substitution occurs at a position that is conserved across species. In silico analysis predicts this variant is probably damaging to the protein structure/function. We interpret Q4203R as a variant of uncertain significance.
Labcorp Genetics (formerly Invitae), Labcorp RCV001865542 SCV002177413 uncertain significance RYR1-related disorder 2021-02-22 criteria provided, single submitter clinical testing 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. 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 expected to disrupt RYR1 protein function. This variant has not been reported in the literature in individuals with RYR1-related conditions. ClinVar contains an entry for this variant (Variation ID: 429565). This variant is present in population databases (rs757438220, ExAC 0.01%). This sequence change replaces glutamine with arginine at codon 4203 of the RYR1 protein (p.Gln4203Arg). The glutamine residue is moderately conserved and there is a small physicochemical difference between glutamine and arginine.
Fulgent Genetics, Fulgent Genetics RCV002481564 SCV002784100 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 2021-08-15 criteria provided, single submitter clinical testing
Revvity Omics, Revvity RCV000494306 SCV003813057 uncertain significance not provided 2023-01-17 criteria provided, single submitter clinical testing
All of Us Research Program, National Institutes of Health RCV004003480 SCV004831253 uncertain significance Malignant hyperthermia, susceptibility to, 1 2023-04-27 criteria provided, single submitter clinical testing

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