Submissions for variant NM_001005242.3(PKP2):c.587G>A (p.Arg196His)

gnomAD frequency: 0.00002  dbSNP: rs146566525

Total submissions: 4

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Labcorp Genetics (formerly Invitae), Labcorp	RCV000703315	SCV000832212	uncertain significance	Arrhythmogenic right ventricular dysplasia 9	2021-09-16	criteria provided, single submitter	clinical testing	This sequence change replaces arginine with histidine at codon 196 of the PKP2 protein (p.Arg196His). The arginine residue is highly conserved and there is a small physicochemical difference between arginine and histidine. This variant is present in population databases (rs146566525, ExAC 0.01%). This variant has not been reported in the literature in individuals affected with PKP2-related conditions. Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be tolerated. 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 Diagnostics, LLC DBA Color Health	RCV001183565	SCV001349355	uncertain significance	Cardiomyopathy	2023-07-27	criteria provided, single submitter	clinical testing	This missense variant replaces arginine with histidine at codon 196 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 4/251168 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.
Ambry Genetics	RCV002352199	SCV002651806	uncertain significance	Cardiovascular phenotype	2021-07-08	criteria provided, single submitter	clinical testing	The p.R196H variant (also known as c.587G>A), located in coding exon 3 of the PKP2 gene, results from a G to A substitution at nucleotide position 587. The arginine at codon 196 is replaced by histidine, an amino acid with highly similar properties. This amino acid position is conserved. 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	RCV003999740	SCV004846507	uncertain significance	Arrhythmogenic right ventricular cardiomyopathy	2023-12-18	criteria provided, single submitter	clinical testing	Variant of Uncertain Significance due to insufficient evidence: This missense variant is located in the head domain of the PKP2 protein. Computational prediction tools and conservation analyses are inconclusive regarding the impact of this variant on the protein function. Computational splicing tools suggest that this variant may not impact RNA splicing. To our knowledge, functional assays have not been performed for this variant nor has this variant been reported in individuals affected with cardiovascular disorders in the literature. This variant has been identified in 3/245970 chromosomes in the general population by the Genome Aggregation Database (gnomAD). Available evidence is insufficient to determine the role of this variant in disease conclusively.