ClinVar Miner

Submissions for variant NM_004572.3(PKP2):c.2537C>A (p.Ser846Tyr) (rs768808114)

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Total submissions: 2
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000183719 SCV000236197 uncertain significance not provided 2017-06-09 criteria provided, single submitter clinical testing The S846Y variant of uncertain significance in the PKP2 gene has not been published as pathogenic or been reported as benign to our knowledge. However, it has been observed in two other unrelated individuals referred for ARVC genetic testing at GeneDx. S846Y is not observed in large population cohorts (Lek et al., 2016; 1000 Genomes Consortium et al., 2015; Exome Variant Server). The S846Y variant is a semi-conservative amino acid substitution, which may impact secondary protein structure as these residues differ in some properties. Yet this substitution occurs at a position that is not conserved. In silico analysis is inconsistent in its predictions as to whether or not the variant is damaging to the protein structure/function.
Invitae RCV000469270 SCV000545249 uncertain significance Arrhythmogenic right ventricular cardiomyopathy, type 9 2016-07-18 criteria provided, single submitter clinical testing This sequence change replaces serine with tyrosine at codon 846 of the PKP2 protein (p.Ser846Tyr). The serine residue is moderately conserved and there is a large physicochemical difference between serine and tyrosine. This variant is not present in population databases (ExAC no frequency) and has not been reported in the literature in individuals with a PKP2-related disease. ClinVar contains an entry for this variant (Variation ID: 201968). 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: "Possibly Damaging"; Align-GVGD: "Class C15"). In summary, this variant is a rare missense change with uncertain impact on protein function. It has been classified as a Variant of Uncertain Significance.

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