ClinVar Miner

Submissions for variant NM_001035.3(RYR2):c.3151C>T (p.Arg1051Cys) (rs533330664)

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Total submissions: 2
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000182708 SCV000235088 uncertain significance not provided 2018-09-10 criteria provided, single submitter clinical testing A variant of uncertain significance has been identified in the RYR2 gene. The R1051C variant has been reported in one patient with cyclic vomiting and fatigue; however, no cardiac features were noted (Lee et al., 2015). Additionally, this variant is observed 20/205652 (0.01%) alleles from individuals of multiple ethnic backgrounds in large population cohorts (Lek et al., 2016). This 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). Nevertheless, the R1051C 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. In-silico analyses, including protein predictors and evolutionary conservation, support a deleterious effect. Therefore, based on the currently available information, it is unclear whether this variant is pathogenic or rare benign.
Laboratory for Molecular Medicine,Partners HealthCare Personalized Medicine RCV000456036 SCV000540259 uncertain significance not specified 2016-12-16 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: This variant has not been reported in affected individuals. It is classified in ClinVar with 1 star as Likely pathogenic by GeneDx. It has a Max MAF of 0.07% in ExAC (7 alleles) and 0.06% in gnomAD (16 alleles). The AA at this position is conserved. In HGMD there is another variant at this position: Arg1051Pro. In GI there are 2 other variants at this position: Arg1051Arg (likely benign) and Arg1051His (VUS4).

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