ClinVar Miner

Submissions for variant NM_004572.3(PKP2):c.1547A>G (p.Lys516Arg) (rs749926313)

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Total submissions: 3
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000183744 SCV000236225 likely pathogenic not provided 2014-03-27 criteria provided, single submitter clinical testing p.Lys516Arg (AAG>AGG): c.1547 A>G in exon 7 of the PKP2 gene (NM_004572.3). It has not been published as a mutation, nor has it been reported as a benign polymorphism to our knowledge. The K526R variant was not observed in approximately 6,500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, indicating it is not a common benign variant in these populations. The K526R variant is a conservative amino acid substitution, which is not likely to impact secondary protein structure as these residues share similar properties. However, this substitution occurs at a position that is conserved across species. In silico analysis predicts this variant is probably damaging to the protein structure/function. A missense mutation in a nearby residue (T526M) has been reported in association with ARVC, supporting the functional importance of this region of the protein. Therefore, this variant is a strong candidate for a pathogenic mutation, however the possibility that it is a benign variant cannot be excluded. The variant is found in ARRHYTHMIA panel(s).
Invitae RCV000640021 SCV000761608 uncertain significance Arrhythmogenic right ventricular cardiomyopathy, type 9 2019-06-24 criteria provided, single submitter clinical testing This sequence change replaces lysine with arginine at codon 516 of the PKP2 protein (p.Lys516Arg). The lysine residue is highly conserved and there is a small physicochemical difference between lysine and arginine. This variant is not present in population databases (ExAC no frequency). This variant has not been reported in the literature in individuals with PKP2-related disease. ClinVar contains an entry for this variant (Variation ID: 201985). 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. Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may create or strengthen a splice site, but this prediction has not been confirmed by published transcriptional studies. 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.
Color RCV001188339 SCV001355376 uncertain significance Cardiomyopathy 2019-06-24 criteria provided, single submitter clinical testing

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