Submissions for variant NM_001005242.3(PKP2):c.2372A>G (p.Lys791Arg)

gnomAD frequency: 0.00003  dbSNP: rs372729739

Total submissions: 4

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Color Diagnostics, LLC DBA Color Health	RCV001176961	SCV001341066	uncertain significance	Cardiomyopathy	2023-01-23	criteria provided, single submitter	clinical testing	This missense variant replaces lysine with arginine at codon 835 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 Brugada syndrome (PMID: 27085656). This variant has been identified in 2/251406 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.
GeneDx	RCV001540718	SCV001758630	uncertain significance	not provided	2019-04-18	criteria provided, single submitter	clinical testing	Identified in one individual with a clinical diagnosis of Brugada syndrome; segregation studies identified the variant in one affected relative and two unaffected relatives (Allegue et al., 2015); Not observed at a significant frequency in large population cohorts (Lek et al., 2016); In silico analysis, which includes protein predictors and evolutionary conservation, supports that this variant does not alter protein structure/function; Observed in conjunction with additional cardiogenetic variants in patients with cardiomyopathy referred for genetic testing at GeneDx; This variant is associated with the following publications: (PMID: 30821013, 27085656, 26230511)
Invitae	RCV001875832	SCV002301698	uncertain significance	Arrhythmogenic right ventricular dysplasia 9	2023-12-13	criteria provided, single submitter	clinical testing	This sequence change replaces lysine, which is basic and polar, with arginine, which is basic and polar, at codon 835 of the PKP2 protein (p.Lys835Arg). This variant is present in population databases (rs372729739, gnomAD 0.003%). This missense change has been observed in individual(s) with Brugada syndrome (PMID: 26230511). ClinVar contains an entry for this variant (Variation ID: 919036). 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. 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	RCV002451359	SCV002738819	uncertain significance	Cardiovascular phenotype	2020-10-19	criteria provided, single submitter	clinical testing	The p.K835R variant (also known as c.2504A>G), located in coding exon 13 of the PKP2 gene, results from an A to G substitution at nucleotide position 2504. The lysine at codon 835 is replaced by arginine, an amino acid with highly similar properties. This variant was detected in an individual with Brugada syndrome, as well as in one affected and two unaffected family members (Allegue C et al. PLoS One, 2015 Jul;10:e0133037). 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.