Submissions for variant NM_001005242.3(PKP2):c.838G>A (p.Val280Ile)

gnomAD frequency: 0.00001  dbSNP: rs748148237

Total submissions: 4

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Color Diagnostics, LLC DBA Color Health	RCV001180933	SCV001345986	uncertain significance	Cardiomyopathy	2023-03-16	criteria provided, single submitter	clinical testing	This missense variant replaces valine with isoleucine at codon 280 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 cardiovascular disorders in the literature. This variant has been identified in 7/250990 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.
Invitae	RCV001876007	SCV002156027	uncertain significance	Arrhythmogenic right ventricular dysplasia 9	2023-09-06	criteria provided, single submitter	clinical testing	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. Algorithms developed to predict the effect of missense changes on protein structure and function output the following: SIFT: "Not Available"; PolyPhen-2: "Benign"; Align-GVGD: "Not Available". The isoleucine amino acid residue is found in multiple mammalian species, which suggests that this missense change does not adversely affect protein function. ClinVar contains an entry for this variant (Variation ID: 921491). This variant has not been reported in the literature in individuals affected with PKP2-related conditions. This variant is present in population databases (rs748148237, gnomAD 0.01%). This sequence change replaces valine, which is neutral and non-polar, with isoleucine, which is neutral and non-polar, at codon 280 of the PKP2 protein (p.Val280Ile).
Ambry Genetics	RCV003380860	SCV004088668	uncertain significance	Cardiovascular phenotype	2023-07-07	criteria provided, single submitter	clinical testing	The p.V280I variant (also known as c.838G>A), located in coding exon 3 of the PKP2 gene, results from a G to A substitution at nucleotide position 838. The valine at codon 280 is replaced by isoleucine, an amino acid with highly similar properties. This amino acid position is poorly 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.
All of Us Research Program, National Institutes of Health	RCV004006701	SCV004846477	uncertain significance	Arrhythmogenic right ventricular cardiomyopathy	2023-06-26	criteria provided, single submitter	clinical testing	This missense variant replaces valine with isoleucine at codon 280 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 cardiovascular disorders in the literature. This variant has been identified in 7/250990 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.