ClinVar Miner

Submissions for variant NM_000540.3(RYR1):c.12886C>T (p.Arg4296Trp)

gnomAD frequency: 0.00035  dbSNP: rs995399684
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Total submissions: 7
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Ambry Genetics RCV000622930 SCV000741931 uncertain significance Inborn genetic diseases 2016-11-10 criteria provided, single submitter clinical testing
Invitae RCV000655522 SCV000777453 uncertain significance RYR1-related disorder 2022-09-26 criteria provided, single submitter clinical testing This sequence change replaces arginine, which is basic and polar, with tryptophan, which is neutral and slightly polar, at codon 4296 of the RYR1 protein (p.Arg4296Trp). This variant is present in population databases (no rsID available, gnomAD 50%). 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: 521376). 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.
PreventionGenetics, part of Exact Sciences RCV000721298 SCV000852325 uncertain significance not provided 2016-08-18 criteria provided, single submitter clinical testing
GeneDx RCV000721298 SCV001795630 uncertain significance not provided 2022-11-16 criteria provided, single submitter clinical testing Has not been previously published as pathogenic or benign to our knowledge; In silico analysis supports that this missense variant does not alter protein structure/function; This variant is associated with the following publications: (PMID: 20681998)
MGZ Medical Genetics Center RCV002289910 SCV002581762 uncertain significance Central core myopathy 2022-08-12 criteria provided, single submitter clinical testing
Fulgent Genetics, Fulgent Genetics RCV002506516 SCV002814315 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 2021-07-26 criteria provided, single submitter clinical testing
Illumina Laboratory Services, Illumina RCV000655522 SCV004035996 uncertain significance RYR1-related disorder 2023-04-20 criteria provided, single submitter clinical testing The RYR1 c.12886C>T (p.Arg4296Trp) missense variant has not, to our knowledge, been reported in the peer-reviewed literature. The highest frequency of this allele in the Genome Aggregation Database is 0.000641 in the African/African American population (version 3.1.2). This frequency is high for autosomal dominant inheritance but may be consistent with autosomal recessive inheritance. Based on the available evidence, the c.12886C>T (p.Arg4296Trp) variant is classified as a variant of uncertain significance for RYR1-related disorders.

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