ClinVar Miner

Submissions for variant NM_000540.2(RYR1):c.2275A>G (p.Asn759Asp) (rs147320363)

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Total submissions: 6
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Biesecker Lab/Clinical Genomics Section,National Institutes of Health RCV000210004 SCV000265693 uncertain significance Malignant hyperthermia, susceptibility to, 1 2013-07-01 criteria provided, single submitter research
CSER_CC_NCGL; University of Washington Medical Center RCV000148816 SCV000190555 uncertain significance Myopathy, RYR1-associated 2014-06-01 no assertion criteria provided research
EGL Genetic Diagnostics,Eurofins Clinical Diagnostics RCV000723802 SCV000203450 uncertain significance not provided 2014-01-06 criteria provided, single submitter clinical testing
GeneDx RCV000723802 SCV000514423 uncertain significance not provided 2018-11-26 criteria provided, single submitter clinical testing The N759D variant in the RYR1 gene has been identified in trans with another variant in a patient with central core disease (Bharucha-Goebel et al., 2013; Amburgey et al., 2013). However, the N759D variant has also been detected in the heterozygous state in individuals with no personal or family history of malignant hyperthermia or myopathy (Gonsalves et al., 2013). The N759D 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 N759D 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, and in silico analysis predicts this variant is probably damaging to the protein structure/function. Therefore, based on the currently available information, it is unclear whether this variant is a pathogenic variant or a rare benign variant.
Invitae RCV000533102 SCV000659885 uncertain significance RYR1-Related Disorders 2018-10-22 criteria provided, single submitter clinical testing This sequence change replaces asparagine with aspartic acid at codon 759 of the RYR1 protein (p.Asn759Asp). The asparagine residue is highly conserved and there is a small physicochemical difference between asparagine and aspartic acid. This variant is present in population databases (rs147320363, ExAC 0.02%). This variant has been reported in the compound heterozygous state in an individual affected with severe, early-onset congenital myopathy (PMID: 23553484). ClinVar contains an entry for this variant (Variation ID: 161369). 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: "Probably Damaging"; Align-GVGD: "Class C0"). In summary, this variant is a rare missense change with uncertain impact on protein function. It has been reported in both the general population and an affected individual with presumed recessive RYR1 myopathy.  This variant has been classified as a Variant of Uncertain Significance.
Laboratory for Molecular Medicine,Partners HealthCare Personalized Medicine RCV000153861 SCV000540250 uncertain significance not specified 2016-03-31 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: Limited reports in probands, reported in unaffected individuals; ExAC: 16/66720 European; ClinVar: 2 VUS

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