ClinVar Miner

Submissions for variant NM_004572.3(PKP2):c.19C>T (p.Pro7Ser) (rs764645176)

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Total submissions: 3
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000183754 SCV000236235 uncertain significance not provided 2013-05-06 criteria provided, single submitter clinical testing p.Pro7Ser (CCA>TCA): c.19 C>T in exon 1 of the PKP2 gene (NM_004572.3). The Pro7Ser variant in the PKP2 gene has not been reported as a disease-causing mutation or as a benign polymorphism to our knowledge. Pro7Ser results in a non-conservative amino acid substitution of a nonpolar Proline residue with a polar Serine residue. Conservation of this residue and this region of the protein throughout evolution could not be assessed due to poor sequence alignment with other species. Mutations in nearby residues have not been reported (Van der Zwaag P et al., 2009) indicating this region of the protein may tolerate change. The Pro7Ser variant was not observed in approximately 5000 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project (average read depth 4X). With the clinical and molecular information available at this time, we cannot definitively determine if Pro7Ser is a disease-causing mutation or a rare benign variant. The variant is found in ARVC panel(s).
Invitae RCV000806892 SCV000946913 uncertain significance Arrhythmogenic right ventricular cardiomyopathy, type 9 2018-12-28 criteria provided, single submitter clinical testing This sequence change replaces proline with serine at codon 7 of the PKP2 protein (p.Pro7Ser). The proline residue is weakly 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 not been reported in the literature in individuals with PKP2-related conditions. ClinVar contains an entry for this variant (Variation ID: 201992). Algorithms developed to predict the effect of missense changes on protein structure and function output the following: SIFT: "Tolerated"; PolyPhen-2: "Benign"; Align-GVGD: "Class C0". The serine amino acid residue is found in multiple mammalian species, suggesting that this missense change does not adversely affect protein function. 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.
Color RCV001190427 SCV001357915 uncertain significance Cardiomyopathy 2019-08-06 criteria provided, single submitter clinical testing

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