Submissions for variant NM_001005242.3(PKP2):c.974C>T (p.Ala325Val)

gnomAD frequency: 0.00005  dbSNP: rs201803918

Total submissions: 6

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Labcorp Genetics (formerly Invitae), Labcorp	RCV000689209	SCV000816849	uncertain significance	Arrhythmogenic right ventricular dysplasia 9	2024-01-22	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 325 of the PKP2 protein (p.Ala325Val). This variant is present in population databases (rs201803918, gnomAD 0.006%). This variant has not been reported in the literature in individuals affected with PKP2-related conditions. ClinVar contains an entry for this variant (Variation ID: 568756). 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 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.
CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario	RCV000770421	SCV000901864	uncertain significance	Cardiomyopathy	2016-03-16	criteria provided, single submitter	clinical testing
Color Diagnostics, LLC DBA Color Health	RCV000770421	SCV001357948	uncertain significance	Cardiomyopathy	2022-12-20	criteria provided, single submitter	clinical testing	This missense variant replaces alanine with valine at codon 325 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, who also carried a pathogenic variant in the SCN5A gene that could explain the observed phenotype (PMID: 31189615). This variant has also been identified in 12/281476 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	RCV001561511	SCV001784133	uncertain significance	not provided	2020-05-19	criteria provided, single submitter	clinical testing	Has not been previously published as pathogenic or benign to our knowledge; In silico analysis, which includes protein predictors and evolutionary conservation, supports that this variant does not alter protein structure/function; Reported in ClinVar as a variant of uncertain significance (ClinVar Variant ID# 568756; Landrum et al., 2016)
Ambry Genetics	RCV002386178	SCV002695391	uncertain significance	Cardiovascular phenotype	2024-05-14	criteria provided, single submitter	clinical testing	The p.A325V variant (also known as c.974C>T), located in coding exon 3 of the PKP2 gene, results from a C to T substitution at nucleotide position 974. The alanine at codon 325 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. Based on the available evidence, the clinical significance of this variant remains unclear.
All of Us Research Program, National Institutes of Health	RCV004004295	SCV004846451	uncertain significance	Arrhythmogenic right ventricular cardiomyopathy	2024-09-23	criteria provided, single submitter	clinical testing	This missense variant replaces alanine with valine at codon 325 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, who also carried a pathogenic variant in the SCN5A gene that could explain the observed phenotype (PMID: 31189615). This variant has also been observed in an individual affected with dilated cardiomyopathy (PMID: 37904629). This variant has also been identified in 12/281476 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.