Submissions for variant NM_001005242.3(PKP2):c.2142del (p.Asn715fs)

dbSNP: rs794729130

Total submissions: 2

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000183797	SCV000236278	likely pathogenic	not provided	2016-04-19	criteria provided, single submitter	clinical testing	The c.2274delG likely pathogenic variant in the PKP2 gene has not been reported as a pathogenic variant or a benign varaint to our knowledge. The c.2274delG variant causes a shift in reading frame starting at codon Asparagine 759, changing it to an Isoleucine, and creating a premature stop codon at position 41 of the new reading frame, denoted p.N759IfsX41. 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. Other frameshift variants in the PKP2 gene have been reported in HGMD in association with ARVC (Stenson et al., 2014).
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	RCV004017465	SCV004848867	pathogenic	Arrhythmogenic right ventricular cardiomyopathy	2022-11-04	criteria provided, single submitter	clinical testing	The p.Asn759IlefsX41 variant in PKP2 has been reported in at least 1 individual with ARVC and in 1 homozygous individual with DCM (van Lint 2019 PMID: 31386562, Al-hassnan 2020 PMID: 32870709). It has also been reported in ClinVar (Variation ID 202023) but was absent from large population studies. This variant is predicted to cause a frameshift, which alters the protein’s amino acid sequence beginning at position 759 and leads to a premature termination codon 41 amino acids downstream. This alteration is then predicted to lead to a truncated or absent protein. Loss of function of the PKP2 gene is an established disease mechanism in autosomal dominant ARVC. In summary, this variant meets criteria to be classified as pathogenic for autosomal dominant ARVC. ACMG/AMP Criteria applied: PVS1, PS4_Supporting, PM2_Supporting.