Submissions for variant NM_001005242.3(PKP2):c.1740G>T (p.Glu580Asp)

gnomAD frequency: 0.00011  dbSNP: rs370219248

Total submissions: 8

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000766574	SCV000236242	uncertain significance	not provided	2023-09-29	criteria provided, single submitter	clinical testing	Reported in a female with sudden unexplained death at 33 years of age; however, this individual also harbored additional variants, including a frameshift variant in the TTN gene considered to be disease-causing (PMID: 27930701); In silico analysis supports that this missense variant does not alter protein structure/function; This variant is associated with the following publications: (PMID: 33500567, 28166282, 31983221, 27930701)
Labcorp Genetics (formerly Invitae), Labcorp	RCV000473176	SCV000545221	uncertain significance	Arrhythmogenic right ventricular dysplasia 9	2023-12-11	criteria provided, single submitter	clinical testing	This sequence change replaces glutamic acid, which is acidic and polar, with aspartic acid, which is acidic and polar, at codon 624 of the PKP2 protein (p.Glu624Asp). This variant is present in population databases (rs370219248, gnomAD 0.01%). This missense change has been observed in individual(s) with clinical features of PKP2-related conditions (PMID: 27930701, 31983221, 33500567). ClinVar contains an entry for this variant (Variation ID: 201999). 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 aspartic acid amino acid residue is found in multiple mammalian species, which suggests that this missense change does not adversely affect protein function. 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	RCV000183761	SCV000698468	uncertain significance	not specified	2018-11-19	criteria provided, single submitter	clinical testing	Variant summary: PKP2 c.1872G>T (p.Glu624Asp) results in a conservative amino acid change in the encoded protein sequence. Five of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 7.7e-05 in 246044 control chromosomes in the gnomAD database, including 1 homozygotes. This frequency is not significantly higher than expected for a pathogenic variant in PKP2 causing Cardiomyopathy (7.7e-05 vs 0.0011), allowing no conclusion about variant significance. c.1872G>T has been reported in the literature in an individual affected with undetermined sudden death (Sanchez_2016). This report does not provide an unequivocal conclusion about association of the variant with Cardiomyopathy. Co-occurrences with other pathogenic variant(s) have been reported (TTN c.30515_17delAAG, p.E10172fs; a Spanish founder mutation in PKP2, c.987del, p.S329RfsX351), providing supporting evidence for a benign role (Sanchez_2016 and an unpublished reference, A. Diez_Juan et al, 2011, http://spo.escardio.org/eslides/view.aspx?eevtid=48&fp=364). However, considering some patients with cardiomyopathies could have complex genotypes in the main desmosomal genes that could develop early and severe phenotypes, the co-occurrence information would not necessarily prove the non-pathogenicity of our variant of interest. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Two ClinVar submissions from clinical diagnostic laboratories (evaluation after 2014) cite the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as VUS-possibly benign.
CeGaT Center for Human Genetics Tuebingen	RCV000766574	SCV001250084	likely benign	not provided	2023-01-01	criteria provided, single submitter	clinical testing	PKP2: BP4
Illumina Laboratory Services, Illumina	RCV000473176	SCV001269281	uncertain significance	Arrhythmogenic right ventricular dysplasia 9	2018-05-01	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	RCV001181144	SCV001346238	uncertain significance	Cardiomyopathy	2023-12-13	criteria provided, single submitter	clinical testing	This missense variant replaces glutamic acid with aspartic acid at codon 624 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 sudden unexplained death (PMID: 27930701). This variant has been identified in 18/251266 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	RCV002408811	SCV002723576	likely benign	Cardiovascular phenotype	2024-04-11	criteria provided, single submitter	clinical testing	This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity.
All of Us Research Program, National Institutes of Health	RCV003996839	SCV004845974	uncertain significance	Arrhythmogenic right ventricular cardiomyopathy	2024-01-03	criteria provided, single submitter	clinical testing	This missense variant replaces glutamic acid with aspartic acid at codon 624 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 sudden unexplained death (PMID: 27930701). This variant has been identified in 18/251266 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.