Submissions for variant NM_001005242.3(PKP2):c.155dup (p.Ser53fs)

dbSNP: rs958681660

Total submissions: 6

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000521655	SCV000621347	likely pathogenic	not provided	2017-10-02	criteria provided, single submitter	clinical testing	Although the c.155dupA likely pathogenic variant in the PKP2 gene has not been reported to our knowledge, this variant causes a shift in reading frame starting at codon serine 53, changing it to a glutamic acid, and creating a premature stop codon at position 33 of the new reading frame, denoted p.Ser53GlufsX33. This variant is expected to result in either an abnormal, truncated protein product or loss of protein from this allele through nonsense-mediated mRNA decay. Multiple other downstream frameshift variants in the PKP2 gene have been reported in Human Gene Mutation Database in association with ARVC (Stenson et al., 2014), indicating that loss of function is a mechanism of disease for this gene. Furthermore, the c.155dupA variant has not been observed in large population cohorts (Lek et al., 2016).
Centre for Mendelian Genomics, University Medical Centre Ljubljana	RCV001197670	SCV001368449	likely pathogenic	Arrhythmogenic right ventricular dysplasia 9	2020-02-07	criteria provided, single submitter	clinical testing	This variant was classified as: Likely pathogenic. The following ACMG criteria were applied in classifying this variant: PVS1,PM2.
Center for Genomics, Ann and Robert H. Lurie Children's Hospital of Chicago	RCV001197670	SCV003920890	likely pathogenic	Arrhythmogenic right ventricular dysplasia 9	2021-03-30	criteria provided, single submitter	clinical testing	PKP2 NM_004572.3 exon 1 p.Ser53Glufs*33 (c.155dupA): This variant has not been reported in the literature and is not present in large control databases. This variant is present in ClinVar (Variation ID:452533). Evolutionary conservation and computational predictive tools for this variant are limited or unavailable. This variant creates a premature stop codon 33 amino acids downstream from this location which results in an absent or abnormal protein. Loss of function variants have been reported in association with disease for this gene (Rasmussen 2014 PMID:24704780). In summary, data on this variant is highly suspicious for disease, but requires further evidence for pathogenicity. Therefore, this variant classified as likely pathogenic.
All of Us Research Program, National Institutes of Health	RCV004003642	SCV004839348	likely pathogenic	Arrhythmogenic right ventricular cardiomyopathy	2023-11-28	criteria provided, single submitter	clinical testing	This variant is predicted to result in loss of protein function through nonsense-mediated decay or protein truncation. Loss of function is an established mechanism of disease (PMID: 33831308, 24704780, 23486541). This variant was identified in a deceased individual with arrhythmogenic cardiomyopathy and in his father with a normal cardiac phenotype (PMID: 34379075). This variant is absent from large population databases, including the Genome Aggregation Database (http://gnomad.broadinstitute.org/).
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	RCV004003642	SCV004847279	likely pathogenic	Arrhythmogenic right ventricular cardiomyopathy	2023-03-10	criteria provided, single submitter	clinical testing	The p.Ser53GlufsX33 variant in PKP2 has not been reported in the literature in individuals with arrhythmogenic right ventricular cardiomyopathy (ARVC), but it has been reported by other clinical laboratories in ClinVar (Variation ID 452533). It was absent from large population studies (gnomAD, v.3.1.2). This variant is predicted to cause a frameshift, which alters the protein’s amino acid sequence beginning at position 53 and leads to a premature termination codon 33 amino acids downstream. Heterozygous loss of function of the PKP2 gene is an established disease mechanism in autosomal dominant right ventricular cardiomyopathy (ARVC). In summary, although additional studies are required to fully establish its clinical significance, this variant meets criteria to be classified as likely pathogenic for autosomal dominant ARVC. ACMG/AMP Criteria applied: PVS1, PM2_Supporting.
Clinical Genetics Laboratory, Skane University Hospital Lund	RCV000521655	SCV005197181	likely pathogenic	not provided	2022-05-27	criteria provided, single submitter	clinical testing