ClinVar Miner

Submissions for variant NM_001035.3(RYR2):c.4747C>T (p.Pro1583Ser) (rs200070226)

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Total submissions: 4
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000766723 SCV000568207 uncertain significance not provided 2017-03-27 criteria provided, single submitter clinical testing A variant of uncertain significance has been identified in the RYR2 gene. The P1583S variant has been published in one patient with ARVC and was inherited from an affected father (Roux-Buisson et al., 2014). This variant is not observed in large population cohorts (Lek et al., 2016; 1000 Genomes Consortium et al., 2015; Exome Variant Server). The P1583S 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 in silico analysis predicts this variant is probably damaging to the protein structure/function. However, the P1583S 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). Furthermore, studies are needed to determine the functional effect of this variant and further clarify its pathogenicity.
Invitae RCV000799104 SCV000938753 uncertain significance Catecholaminergic polymorphic ventricular tachycardia 2018-11-07 criteria provided, single submitter clinical testing This sequence change replaces proline with serine at codon 1583 of the RYR2 protein (p.Pro1583Ser). The proline residue is highly conserved and there is a moderate physicochemical difference between proline and serine. The frequency data for this variant in the population databases is considered unreliable, as metrics indicate poor data quality at this position in the ExAC database. This variant has been observed in a family affected with arrhythmogenic right ventricular cardiomyopathy (PMID: 25041964). Additionally, the variant has been observed in an individual affected with suspected sudden cardiac death (PMID: 26383259). ClinVar contains an entry for this variant (Variation ID: 419965). Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be disruptive, but these predictions have not been confirmed by published functional studies and their clinical significance is uncertain. 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.
Laboratory for Molecular Medicine,Partners HealthCare Personalized Medicine RCV000482205 SCV000732034 uncertain significance not specified 2017-12-15 criteria provided, single submitter clinical testing The p.Pro1583Ser variant in RYR2 has been reported in the literature in 1 indivi dual with SCD and 1 individual with ARVC. For the patient with ARVC, the variant segregated with disease in 1 affected relative and 1 relative with borderline c linical features (Roux-Buisson 2014, Hertz 2016). The variant has also been iden tified in 13/34114 Latino chromosomes and 11/125230 European chromosomes by the Genome Aggregation Database (gnomAD, http://gnomad.broadinstitute.org/; dbSNP rs 200070226). This variant has also been reported in ClinVar (Variation ID:419965) . Computational prediction tools and conservation analysis suggest that the p.Pr o1583Ser variant may impact the protein, though this information is not predicti ve enough to determine pathogenicity. In summary, while there is some suspicion for a pathogenic role, the clinical significance of the p.Pro1583Ser variant is uncertain. ACMG/AMP Criteria applied: PP3; PS4_Supporting.
Lupski Lab, Baylor-Hopkins CMG, Baylor College of Medicine RCV000656153 SCV000678347 uncertain significance Wolff-Parkinson-White pattern 2017-07-14 no assertion criteria provided research This variant was identified in an individual with Wolff-Parkinson-White syndrome

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