ClinVar Miner

Submissions for variant NM_000540.3(RYR1):c.10204T>G (p.Cys3402Gly) (rs367543058)

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Total submissions: 8
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Genetic Services Laboratory,University of Chicago RCV000147397 SCV000194776 pathogenic not provided 2013-12-02 criteria provided, single submitter clinical testing
Center for Genetic Medicine Research,Children's National Medical Center RCV000233916 SCV000265781 likely pathogenic Central core myopathy 2015-12-01 criteria provided, single submitter research
EGL Genetic Diagnostics,Eurofins Clinical Diagnostics RCV000147397 SCV000335753 uncertain significance not provided 2015-10-19 criteria provided, single submitter clinical testing
GeneDx RCV000147397 SCV000521246 likely pathogenic not provided 2016-12-13 criteria provided, single submitter clinical testing A variant that is likely pathogenic has been identified in the RYR1 gene. The C3402G variant has been previously reported in an individual with congenital fiber type disproportion, who harbored an additional pathogenic variant on the opposite RYR1 allele (Clarke et al., 2010). The C3402G 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). This variant is a non-conservative amino acid substitution, which is likely to impact secondary protein structure as these residues differ in polarity, charge, size and/or other properties. This substitution occurs at a position that is conserved across species, and missense variants in a nearby residue (A3407S/T) have been reported in the Human Gene Mutation Database in association with rhabdomyolysis (Stenson et al., 2014). Additionally, in silico analysis predicts this variant is probably damaging to the protein structure/function. Therefore, this variant is likely pathogenic; however, the possibility that it is benign cannot be excluded.
Laboratory for Molecular Medicine, Partners HealthCare Personalized Medicine RCV000401146 SCV000540253 uncertain significance not specified 2016-08-12 criteria provided, single submitter clinical testing Variant identified in a genome or exome case(s) and assessed due to predicted null impact of the variant or pathogenic assertions in the literature or databases. Disclaimer: This variant has not undergone full assessment. The following are preliminary notes: Only reported in association with myopathy (congenital fiber type disproportion), in only 1 proband.
Invitae RCV000529599 SCV000659742 pathogenic RYR1-Related Disorders 2019-12-23 criteria provided, single submitter clinical testing This sequence change replaces cysteine with glycine at codon 3402 of the RYR1 protein (p.Cys3402Gly). The cysteine residue is highly conserved and there is a large physicochemical difference between cysteine and glycine. This variant is present in population databases (rs367543058, ExAC 0.005%). This variant has been reported to occur in trans with a pathogenic variant in an individual affected with congenital fiber type disproportion (CFTD) (PMID: 20583297). This variant has also been identified in trans with a second RYR1 likely pathogenic or pathogenic variant in individuals affected with severe hypotonia and congenital muscle weakness (Invitae). In addition, this variant has been reported in the heterozygous state in three individuals affected with CFTD (PMID: 27854218, Invitae). ClinVar contains an entry for this variant (Variation ID: 42098). Algorithms developed to predict the effect of missense changes on protein structure and function do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Benign"; Align-GVGD: "Class C0"). For these reasons, this variant has been classified as Pathogenic.
CeGaT Praxis fuer Humangenetik Tuebingen RCV000147397 SCV001246301 likely pathogenic not provided 2020-02-01 criteria provided, single submitter clinical testing
GeneReviews RCV000034925 SCV000058532 pathologic Congenital myopathy with fiber type disproportion 2013-04-11 no assertion criteria provided curation Converted during submission to Pathogenic.

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