Submissions for variant NM_001005242.3(PKP2):c.307C>A (p.Pro103Thr)

gnomAD frequency: 0.00016  dbSNP: rs139215336

Total submissions: 10

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000727359	SCV000515737	uncertain significance	not provided	2024-03-29	criteria provided, single submitter	clinical testing	In silico analysis supports that this missense variant does not alter protein structure/function; This variant is associated with the following publications: (PMID: 24704780, 25351510, 27532257)
Labcorp Genetics (formerly Invitae), Labcorp	RCV000530560	SCV000638897	uncertain significance	Arrhythmogenic right ventricular dysplasia 9	2024-01-16	criteria provided, single submitter	clinical testing	This sequence change replaces proline, which is neutral and non-polar, with threonine, which is neutral and polar, at codon 103 of the PKP2 protein (p.Pro103Thr). This variant is present in population databases (rs139215336, gnomAD 0.02%). This missense change has been observed in individual(s) with arrhythmogenic cardiomyopathy and hypertrophic cardiomyopathy (PMID: 24704780, 25351510). ClinVar contains an entry for this variant (Variation ID: 379132). 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.
Eurofins Ntd Llc (ga)	RCV000727359	SCV000707849	uncertain significance	not provided	2017-04-14	criteria provided, single submitter	clinical testing
Ambry Genetics	RCV000620133	SCV000737751	uncertain significance	Cardiovascular phenotype	2023-10-03	criteria provided, single submitter	clinical testing	The p.P103T variant (also known as c.307C>A), located in coding exon 2 of the PKP2 gene, results from a C to A substitution at nucleotide position 307. The proline at codon 103 is replaced by threonine, an amino acid with highly similar properties. This variant was previously detected in conjunction with another alteration in the DSC2 gene in a proband with arrhythmogenic cardiomyopathy (Rasmussen TB et al. Circ Cardiovasc Genet. 2014;7:230-40). This variant was also reported in a hypertrophic cardiomyopathy cohort; however, clinical details were limited (Lopes LR et al. Heart, 2015 Feb;101:294-301). This amino acid position is well 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.
CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario	RCV000769397	SCV000900789	benign	Cardiomyopathy	2023-03-02	criteria provided, single submitter	clinical testing
Illumina Laboratory Services, Illumina	RCV000530560	SCV001271395	uncertain significance	Arrhythmogenic right ventricular dysplasia 9	2019-06-19	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	RCV000769397	SCV001354749	uncertain significance	Cardiomyopathy	2023-11-20	criteria provided, single submitter	clinical testing	This missense variant replaces proline with threonine at codon 103 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 arrhythmogenic cardiomyopathy (PMID: 24704780) and in an individual affected with hypertrophic cardiomyopathy (PMID: 25351510). This variant has also been identified in 37/282822 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.
Fulgent Genetics, Fulgent Genetics	RCV000530560	SCV002794241	uncertain significance	Arrhythmogenic right ventricular dysplasia 9	2022-02-03	criteria provided, single submitter	clinical testing
All of Us Research Program, National Institutes of Health	RCV003996016	SCV004846547	uncertain significance	Arrhythmogenic right ventricular cardiomyopathy	2024-01-11	criteria provided, single submitter	clinical testing	This missense variant replaces proline with threonine at codon 103 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 arrhythmogenic cardiomyopathy (PMID: 24704780) and in an individual affected with hypertrophic cardiomyopathy (PMID: 25351510). This variant has also been identified in 37/282822 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.
PreventionGenetics, part of Exact Sciences	RCV004742416	SCV005344629	uncertain significance	PKP2-related disorder	2024-06-18	no assertion criteria provided	clinical testing	The PKP2 c.307C>A variant is predicted to result in the amino acid substitution p.Pro103Thr. This variant was reported in an individual with arrhythmogenic cardiomyopathy, although that patient also carried a missense variant in the DSC2 gene (Rasmussen et al. 2014. PubMed ID: 24704780). Additionally, this variant was reported in an individual with hypertrophic cardiomyopathy (Lopes et al. 2014. PubMed ID: 25351510). This variant is reported in 0.024% of alleles in individuals of European (Non-Finnish) descent in gnomAD. At this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence.