ClinVar Miner

Submissions for variant NM_001005242.3(PKP2):c.193G>T (p.Ala65Ser)

gnomAD frequency: 0.00002  dbSNP: rs143323961
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Total submissions: 5
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine RCV000038190 SCV000061857 uncertain significance not specified 2013-02-22 criteria provided, single submitter clinical testing The Ala65Ser variant in PKP2 has been reported in one proband with ARVD/C and wa s absent from 600 control chromosomes (Fressart 2010). The frequency of this var iant in large European American and African American populations screened by the NHLBI Exome Sequencing Project (http://evs.gs.washington.edu/EVS/) cannot be de termined because coverage at this position was insufficient or unavailable. Alan ine at position 65 is conserved in mammals and frog but not in more distant spec ies (zebrafish carries the variant amino acid, serine). This does not rule out a disease causing role. Additional information is needed to fully assess the vari ant's clinical significance.
Illumina Laboratory Services, Illumina RCV001109592 SCV001266944 uncertain significance Arrhythmogenic right ventricular dysplasia 9 2017-04-27 criteria provided, single submitter clinical testing This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). Publications were found based on this search. However, the evidence from the literature, in combination with allele frequency data from public databases where available, was not sufficient to rule this variant in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance.
Color Diagnostics, LLC DBA Color Health RCV001183724 SCV001349534 uncertain significance Cardiomyopathy 2023-01-27 criteria provided, single submitter clinical testing This missense variant replaces alanine with serine at codon 65 of the PKP2 protein. Computational prediction suggests that this variant may not impact protein structure and function (internally defined REVEL score threshold <= 0.5, PMID: 27666373). To our knowledge, functional studies have not been reported for this variant. This variant has been reported in an individual affected with arrhythmogenic right ventricular cardiomyopathy (PMID: 20400443). This variant has not been identified in the general population by the Genome Aggregation Database (gnomAD). The available evidence is insufficient to determine the role of this variant in disease conclusively. Therefore, this variant is classified as a Variant of Uncertain Significance.
Invitae RCV001109592 SCV002290017 uncertain significance Arrhythmogenic right ventricular dysplasia 9 2022-07-06 criteria provided, single submitter clinical testing This sequence change replaces alanine, which is neutral and non-polar, with serine, which is neutral and polar, at codon 65 of the PKP2 protein (p.Ala65Ser). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with arrhythmogenic right ventricular cardiomyopathy, left ventricular non-compaction, and/or unspecified arrhythmia (PMID: 20400443, 30847666, 33500567). ClinVar contains an entry for this variant (Variation ID: 45050). Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Tolerated"; PolyPhen-2: "Possibly 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.
Ambry Genetics RCV003162332 SCV003866168 uncertain significance Cardiovascular phenotype 2022-12-13 criteria provided, single submitter clinical testing The p.A65S variant (also known as c.193G>T), located in coding exon 1 of the PKP2 gene, results from a G to T substitution at nucleotide position 193. The alanine at codon 65 is replaced by serine, an amino acid with similar properties. This variant has been detected in an individual from an arrhythmogenic right ventricular cardiomyopathy cohort, and in individuals who underwent testing for unknown arrhythmia and left ventricular noncompaction; however, clinical details were limited (Fressart V et al. Europace, 2010 Jun;12:861-8; van Lint FHM et al. Neth Heart J, 2019 Jun;27:304-309; Mazzarotto F et al. Genet Med, 2021 May;23:856-864). This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be tolerated by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear.

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