Submissions for variant NM_001005242.3(PKP2):c.1379-1972G>A

gnomAD frequency: 0.00002  dbSNP: rs779392697

Total submissions: 9

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Labcorp Genetics (formerly Invitae), Labcorp	RCV000232479	SCV000288592	uncertain significance	Arrhythmogenic right ventricular dysplasia 9	2024-01-26	criteria provided, single submitter	clinical testing	This sequence change falls in intron 6 of the PKP2 gene. It does not directly change the encoded amino acid sequence of the PKP2 protein. It affects a nucleotide within the consensus splice site. This variant is present in population databases (rs779392697, gnomAD 0.01%). This variant has been observed in individual(s) with dilated cardiomyopathy and/or arrhythmogenic cardiomyopathy (PMID: 32826072, 35819174). ClinVar contains an entry for this variant (Variation ID: 239953). Variants that disrupt the consensus splice site are a relatively common cause of aberrant splicing (PMID: 17576681, 9536098). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus 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.
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	RCV000603241	SCV000710873	uncertain significance	not specified	2017-12-29	criteria provided, single submitter	clinical testing	The c.1510+5G>A variant in PKP2 has not been reported in the literature, but was identified in 3/27754 of Latino and 3/91752 of European chromosomes by the Geno me Aggregation Database (gnomAD, http://gnomad.broadinstitute.org; dbSNP rs77939 2697). This variant has also been reported in ClinVar (Variation ID:239953). Thi s variant is located in the 5' splice region. Computational tools suggest some i mpact to splicing. However, this information is not predictive enough to determi ne pathogenicity. In summary, the clinical significance of the c.1510+5G>A varia nt is uncertain. ACMG/AMP Criteria applied: PP3.
Color Diagnostics, LLC DBA Color Health	RCV001177095	SCV001341229	uncertain significance	Cardiomyopathy	2023-05-10	criteria provided, single submitter	clinical testing	This variant causes a G>A nucleotide substitution at the +5 position of intron 6 of the PKP2 gene. Splice site prediction tools predict that this variant may have a significant impact on RNA splicing. To our knowledge, RNA studies have not been performed for this variant. This variant has not been reported in individuals affected with cardiovascular disorders in the literature. This variant has been identified in 5/211564 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.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000603241	SCV001370650	uncertain significance	not specified	2021-11-15	criteria provided, single submitter	clinical testing	Variant summary: PKP2 c.1510+5G>A 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. Several computational tools predict a significant impact on normal splicing: Two predict the variant abolishes the canonical 5' splicing donor site. Two predict the variant weakens the canonical 5' splice donor site. However, these predictions have yet to be confirmed by functional studies. The variant allele was found at a frequency of 1.1e-05 in 181044 control chromosomes. The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.1510+5G>A has been reported in the literature in a study of individuals enrolled in MyCode Community Health Initiative of Geisinger Health System (GHS), an IRB-approved research biorepository and precision medicine project (Haggerty_2017). These report(s) do not provide unequivocal conclusions about association of the variant with Cardiomyopathy. At-least two co-occurrences with other pathogenic variant(s) have been reported at our laboratory (HCM-MYBPC3 c.1505G>A, p.Arg502Gln; ARVD-PKP2 c.2509delA, p.Ser837fs), providing supporting evidence for a benign role. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Four clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All laboratories classified the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as VUS-possibly benign.
CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario	RCV001177095	SCV002043313	uncertain significance	Cardiomyopathy	2021-05-28	criteria provided, single submitter	clinical testing
Ambry Genetics	RCV002392702	SCV002709767	likely benign	Cardiovascular phenotype	2023-10-18	criteria provided, single submitter	clinical testing	This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, 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.
Breakthrough Genomics, Breakthrough Genomics	RCV001531777	SCV005191753	uncertain significance	not provided		criteria provided, single submitter	not provided
Genome Diagnostics Laboratory, University Medical Center Utrecht	RCV001531777	SCV001930272	uncertain significance	not provided		no assertion criteria provided	clinical testing
Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	RCV001531777	SCV001958592	uncertain significance	not provided		no assertion criteria provided	clinical testing