Submissions for variant NM_001005242.3(PKP2):c.1415A>G (p.Lys472Arg)

dbSNP: rs749926313

Total submissions: 4

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Labcorp Genetics (formerly Invitae), Labcorp	RCV000640021	SCV000761608	uncertain significance	Arrhythmogenic right ventricular dysplasia 9	2022-01-15	criteria provided, single submitter	clinical testing	Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be disruptive. ClinVar contains an entry for this variant (Variation ID: 201985). This variant has not been reported in the literature in individuals affected with PKP2-related conditions. This variant is not present in population databases (gnomAD no frequency). This sequence change replaces lysine, which is basic and polar, with arginine, which is basic and polar, at codon 516 of the PKP2 protein (p.Lys516Arg). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may create or strengthen a splice site. 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.
Color Diagnostics, LLC DBA Color Health	RCV001188339	SCV001355376	uncertain significance	Cardiomyopathy	2019-06-24	criteria provided, single submitter	clinical testing	This missense variant replaces lysine with arginine at codon 516 of the PKP2 protein. Computational prediction tools and conservation analyses suggest that this variant may have deleterious impact on the protein function. Computational splicing tools suggest that this variant may not impact RNA splicing. To our knowledge, functional assays have not been performed for this variant nor has this variant been reported in individuals affected with cardiovascular disorders in the literature. This variant has not been identified in the general population by the Genome Aggregation Database (gnomAD). 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	RCV002399680	SCV002707407	uncertain significance	Cardiovascular phenotype	2021-06-24	criteria provided, single submitter	clinical testing	The p.K516R variant (also known as c.1547A>G), located in coding exon 7 of the PKP2 gene, results from an A to G substitution at nucleotide position 1547. The lysine at codon 516 is replaced by arginine, an amino acid with highly similar properties. This amino acid position is highly conserved in available vertebrate species. In addition, the in silico prediction for this alteration is inconclusive. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear.
GeneDx	RCV000183744	SCV000236225	likely pathogenic	not provided	2014-03-27	flagged submission	clinical testing	p.Lys516Arg (AAG>AGG): c.1547 A>G in exon 7 of the PKP2 gene (NM_004572.3). It has not been published as a mutation, nor has it been reported as a benign polymorphism to our knowledge. The K526R variant was not observed in approximately 6,500 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 K526R variant is a conservative amino acid substitution, which is not likely to impact secondary protein structure as these residues share similar properties. However, this substitution occurs at a position that is conserved across species. In silico analysis predicts this variant is probably damaging to the protein structure/function. A missense mutation in a nearby residue (T526M) has been reported in association with ARVC, supporting the functional importance of this region of the protein. Therefore, this variant is a strong candidate for a pathogenic mutation, however the possibility that it is a benign variant cannot be excluded. The variant is found in ARRHYTHMIA panel(s).