ClinVar Miner

Submissions for variant NM_004572.3(PKP2):c.1876T>A (p.Tyr626Asn) (rs794729112)

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Total submissions: 3
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000183762 SCV000236243 uncertain significance not provided 2018-04-10 criteria provided, single submitter clinical testing The Y626N variant of uncertain significance in the PKP2 gene has not been published as pathogenic or benign to our knowledge. The Y626N variant is a semi-conservative amino acid substitution, which may impact secondary protein structure as these residues differ in some properties. In-silico analyses, including protein predictors and evolutionary conservation, support a deleterious effect. In addition, Y626N is not observed at a significant frequency in large population cohorts (Lek et al., 2016). Moreover, Y626N has been identified independently and/or in conjunction with additional cardiogenetic variants in other individuals referred for genetic testing at GeneDx; however, segregation data is absent for these individuals due to the lack of clinical information provided and insufficient participation by informative family members.
Ambry Genetics RCV000617549 SCV000738225 uncertain significance Cardiovascular phenotype 2017-11-27 criteria provided, single submitter clinical testing Insufficient evidence
Invitae RCV000640019 SCV000761606 uncertain significance Arrhythmogenic right ventricular cardiomyopathy, type 9 2017-11-18 criteria provided, single submitter clinical testing This sequence change replaces tyrosine with asparagine at codon 626 of the PKP2 protein (p.Tyr626Asn). The tyrosine residue is highly conserved and there is a large physicochemical difference between tyrosine and asparagine. This variant is present in population databases (rs794729112, ExAC 0.001%). This variant has not been reported in the literature in individuals with PKP2-related disease. ClinVar contains an entry for this variant (Variation ID: 202000). 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: "Tolerated"; PolyPhen-2: "Probably Damaging"; Align-GVGD: "Class C0"). 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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