Submissions for variant NM_001005242.3(PKP2):c.194C>T (p.Ala65Val)

gnomAD frequency: 0.00008  dbSNP: rs139924723

Total submissions: 5

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Labcorp Genetics (formerly Invitae), Labcorp	RCV000705222	SCV000834209	uncertain significance	Arrhythmogenic right ventricular dysplasia 9	2025-01-29	criteria provided, single submitter	clinical testing	This sequence change replaces alanine, which is neutral and non-polar, with valine, which is neutral and non-polar, at codon 65 of the PKP2 protein (p.Ala65Val). This variant is present in population databases (rs139924723, gnomAD 0.03%). This missense change has been observed in individual(s) with PKP2-related conditions (internal data). ClinVar contains an entry for this variant (Variation ID: 581408). An algorithm developed to predict the effect of missense changes on protein structure and function (PolyPhen-2) suggests that this variant is likely to be disruptive. This variant disrupts the p.Ala65 amino acid residue in PKP2. Other variant(s) that disrupt this residue have been observed in individuals with PKP2-related conditions (PMID: 20400443), which suggests that this may be a clinically significant amino acid residue. 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.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV001193940	SCV001363119	uncertain significance	not specified	2019-04-29	criteria provided, single submitter	clinical testing	Variant summary: PKP2 c.194C>T (p.Ala65Val) results in a non-conservative amino acid change in the encoded protein sequence. Four of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 2.9e-05 in 205336 control chromosomes (gnomAD). The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. To our knowledge, no occurrence of c.194C>T in individuals affected with Cardiomyopathy and no experimental evidence demonstrating its impact on protein function have been reported. One submitter has provided clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation and classified the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as uncertain significance.
Ambry Genetics	RCV002422599	SCV002718270	uncertain significance	Cardiovascular phenotype	2022-06-02	criteria provided, single submitter	clinical testing	The p.A65V variant (also known as c.194C>T), located in coding exon 1 of the PKP2 gene, results from a C to T substitution at nucleotide position 194. The alanine at codon 65 is replaced by valine, an amino acid with similar properties. This amino acid position is highly conserved in available vertebrate species. In addition, the in silico prediction for this alteration is inconclusive. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear.
Color Diagnostics, LLC DBA Color Health	RCV003532250	SCV004358931	uncertain significance	Cardiomyopathy	2023-05-12	criteria provided, single submitter	clinical testing	This missense variant replaces alanine with valine 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 not been reported in individuals affected with PKP2-related disorders in the literature. This variant has been identified in 7/236698 chromosomes 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.
All of Us Research Program, National Institutes of Health	RCV003999765	SCV004823901	uncertain significance	Arrhythmogenic right ventricular cardiomyopathy	2024-04-16	criteria provided, single submitter	clinical testing	This missense variant replaces alanine with valine 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 not been reported in individuals affected with PKP2-related disorders in the literature. This variant has been identified in 7/236698 chromosomes 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.