ClinVar Miner

Submissions for variant NM_001035.3(RYR2):c.9518C>T (p.Thr3173Ile) (rs746161154)

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Total submissions: 4
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Ambry Genetics RCV000621590 SCV000736733 uncertain significance Cardiovascular phenotype 2018-04-02 criteria provided, single submitter clinical testing Lines of evidence used in support of classification: Insufficient evidence
Color RCV000778054 SCV000914169 uncertain significance Cardiomyopathy 2018-10-15 criteria provided, single submitter clinical testing Variant of Uncertain Significance due to insufficient evidence: This missense variant is located in the cytoplasmic domain of the RYR2 protein. Computational prediction tools and conservation analyses suggest that this variant may have deleterious impact on the protein function. Computational splicing tools suggest that this variant may not impact RNA splicing. To our knowledge, functional assays have not been performed for this variant nor has this variant been reported in individuals affected with cardiovascular disorders in the literature. This variant has been identified in 10/262578 chromosomes (10/22984 African chromosomes) in the general population by the Genome Aggregation Database (gnomAD). Available evidence is insufficient to determine the pathogenicity of this variant conclusively.
GeneDx RCV000182778 SCV000235164 uncertain significance not provided 2015-11-16 criteria provided, single submitter clinical testing The T3173I variant has not been published as a pathogenic variant or been reported as a benign variant to our knowledge. The T3173I variant was not observed in approximately 6,000 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, indicating it is not a common benign variant in these populations. In addition, the T3173I 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. Furthermore, this substitution occurs at a position that is conserved in mammals. Nevertheless, in silico analysis is inconsistent in its predictions as to whether or not the variant is damaging to the protein structure/function. Moreover, no missense variants in nearby residues have been reported in the Human Gene Mutation Database in association with RYR2-related disorders (Stenson et al., 2014), and the T3173I variant is not located in one of the three hot-spot regions of the RYR2 gene, where the majority of pathogenic missense variants occur (Medeiros-Domingo et al., 2009). Therefore, based on the currently available information, it is unclear whether this variant is a pathogenic variant or a rare benign variant.
Invitae RCV000689654 SCV000817317 uncertain significance Catecholaminergic polymorphic ventricular tachycardia 2018-05-29 criteria provided, single submitter clinical testing This sequence change replaces threonine with isoleucine at codon 3173 of the RYR2 protein (p.Thr3173Ile). The threonine residue is highly conserved and there is a moderate physicochemical difference between threonine and isoleucine. This variant is present in population databases (rs746161154, ExAC 0.01%). This variant has been observed in an individual referred for genetic testing (PMID: 28404607). ClinVar contains an entry for this variant (Variation ID: 201295). Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Benign"; Align-GVGD: "Class C65"). 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.

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