Submissions for variant NM_001005242.3(PKP2):c.2013A>G (p.Pro671=)

dbSNP: rs1956373944

Total submissions: 4

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Color Diagnostics, LLC DBA Color Health	RCV001182305	SCV001347710	likely benign	Cardiomyopathy	2018-11-25	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV001193944	SCV001363123	uncertain significance	not specified	2019-10-08	criteria provided, single submitter	clinical testing	Variant summary: PKP2 c.2145A>G (p.Pro715Pro) alters a non-conserved nucleotide located close to a canonical splice site and therefore could affect mRNA splicing, leading to a significantly altered protein sequence. 4/4 computational tools predict no significant impact on normal splicing. However, these predictions have yet to be confirmed by functional studies. The variant was absent in 251390 control chromosomes. The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. To our knowledge, no occurrence of c.2145A>G in individuals affected with Arrhythmia/ARVD/SCD/Cardiomyopathy and no experimental evidence demonstrating its impact on protein function have been reported. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014. Based on the evidence outlined above, the variant was classified as VUS-possibly benign.
Ambry Genetics	RCV002429815	SCV002730294	likely benign	Cardiovascular phenotype	2020-08-25	criteria provided, single submitter	clinical testing	This alteration is classified as likely benign based on a combination of the following: 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.
Invitae	RCV003617903	SCV004524442	uncertain significance	Arrhythmogenic right ventricular dysplasia 9	2023-06-24	criteria provided, single submitter	clinical testing	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. Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant is not likely to affect RNA splicing. ClinVar contains an entry for this variant (Variation ID: 922293). 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 affects codon 715 of the PKP2 mRNA. It is a 'silent' change, meaning that it does not change the encoded amino acid sequence of the PKP2 protein. It affects a nucleotide within the consensus splice site.