Submissions for variant NM_001005242.3(PKP2):c.250C>T (p.Pro84Ser)

dbSNP: rs756468173

Total submissions: 5

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000445111	SCV000514124	uncertain significance	not provided	2016-10-24	criteria provided, single submitter	clinical testing	A variant of uncertain significance has been identified in the PKP2 gene. The P84S variant has not been published as a pathogenic variant, nor has it been reported as a benign variant to our knowledge. The P84S variant was not observed in approximately 6500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, indicating it is not a common benign variant in these populations. The P84S variant is a non-conservative amino acid substitution, which is likely to impact secondary protein structure as these residues differ in polarity, charge, size and/or other properties, and this substitution occurs at a position that is conserved across species. Additionally, the majority of in silico algorithims (2 out of 3) predict this variant is probably damaging to the protein structure/function.
Color Diagnostics, LLC DBA Color Health	RCV001188690	SCV001355816	uncertain significance	Cardiomyopathy	2023-12-08	criteria provided, single submitter	clinical testing	This missense variant replaces proline with serine at codon 84 of the PKP2 protein. Computational prediction is inconclusive regarding the impact of this variant on protein structure and function (internally defined REVEL score threshold 0.5 < inconclusive < 0.7, PMID: 27666373). To our knowledge, functional studies have not been reported for this variant. This variant has been reported in an individual affected with dilated cardiomyopathy and in an healthy control individual (PMID: 31983221). This variant has been identified in 1/251406 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.
Labcorp Genetics (formerly Invitae), Labcorp	RCV001210784	SCV001382289	uncertain significance	Arrhythmogenic right ventricular dysplasia 9	2024-11-13	criteria provided, single submitter	clinical testing	This sequence change replaces proline, which is neutral and non-polar, with serine, which is neutral and polar, at codon 84 of the PKP2 protein (p.Pro84Ser). This variant is present in population databases (rs756468173, gnomAD 0.0009%). 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: 378367). 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.
All of Us Research Program, National Institutes of Health	RCV003995974	SCV004844462	uncertain significance	Arrhythmogenic right ventricular cardiomyopathy	2023-12-18	criteria provided, single submitter	clinical testing	This missense variant replaces proline with serine at codon 84 of the PKP2 protein. Computational prediction is inconclusive regarding the impact of this variant on protein structure and function (internally defined REVEL score threshold 0.5 < inconclusive < 0.7, PMID: 27666373). Splice site prediction tools suggest that this variant may not impact RNA splicing. 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 1/251406 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.
Ambry Genetics	RCV004984865	SCV005476549	uncertain significance	Cardiovascular phenotype	2024-08-22	criteria provided, single submitter	clinical testing	The p.P84S variant (also known as c.250C>T), located in coding exon 2 of the PKP2 gene, results from a C to T substitution at nucleotide position 250. The proline at codon 84 is replaced by serine, an amino acid with similar properties. This variant has been detected in an individual from a dilated cardiomyopathy cohort, and in a healthy control; however, details were limited (Mazzarotto F et al. Circulation, 2020 Feb;141:387-398). 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.