Submissions for variant NM_001005242.3(PKP2):c.1211dup (p.Val406fs)

dbSNP: rs397516989

Total submissions: 11

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	RCV000038154	SCV000061820	pathogenic	Arrhythmogenic right ventricular cardiomyopathy	2019-01-18	criteria provided, single submitter	clinical testing	The p.Val406SerfsX4 variant in PKP2 has been identified in >15 individuals with ARVC, the majority of whom were Dutch (van Tintelen 2006, Groeneweg 2013, Orgero n 2017, Proost 2017, Walsh 2017, LMM data). It was also identified in the homozy gous state in 2 siblings with hypoplastic left heart syndrome (Verhagen 2018). I t was absent from large population studies. This variant is predicted to cause a frameshift, which alters the protein?s amino acid sequence beginning at positio n 406 and leads to a premature termination codon 4 amino acids downstream. This alteration is then predicted to lead to a truncated or absent protein. Loss of f unction of the PKP2 gene is an established disease mechanism in autosomal domina nt ARVC. In summary, this variant meets criteria to be classified as pathogenic for autosomal dominant ARVC. ACMG/AMP criteria applied: PVS1, PS4, PM2.
Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	RCV000603676	SCV000744702	pathogenic	Arrhythmogenic right ventricular dysplasia 9	2015-09-21	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV001841581	SCV000920004	pathogenic	Cardiac arrhythmia	2017-11-15	criteria provided, single submitter	clinical testing	Variant summary: The PKP2 c.1211dupT (p.Val406SerfsX4) variant results in a premature termination codon, predicted to cause a truncated or absent PKP2 protein due to nonsense mediated decay, which are commonly known mechanisms for disease. Truncations downstream of this position have been classified as pathogenic by our laboratory (e.g. c.1613G>A/ p.Trp538X). One in silico tool predicts a damaging outcome for this variant. This variant is absent in 246050 control chromosomes. This variant has been reported in multiple confirmed ARVD patients, some of whom have a strong family history. Taken together, this variant is classified as pathogenic.
Labcorp Genetics (formerly Invitae), Labcorp	RCV000603676	SCV000959255	pathogenic	Arrhythmogenic right ventricular dysplasia 9	2025-01-14	criteria provided, single submitter	clinical testing	This sequence change creates a premature translational stop signal (p.Val406Serfs*4) in the PKP2 gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in PKP2 are known to be pathogenic (PMID: 15489853, 17041889, 23911551). This variant is not present in population databases (gnomAD no frequency). This premature translational stop signal has been observed in individuals with arrhythmogenic rightventricular dysplasia/cardiomyopathy and arrhythmogenic right ventricular dysplasia/cardiomyopathy (PMID: 16567567, 23871674, 27532257). It has also been observed to segregate with disease in related individuals. This variant is also known as 1211–1212insT (Val406SerfsX3) and c.1211dup p.(Val406fs). ClinVar contains an entry for this variant (Variation ID: 45015). For these reasons, this variant has been classified as Pathogenic.
MGZ Medical Genetics Center	RCV000603676	SCV002580541	pathogenic	Arrhythmogenic right ventricular dysplasia 9	2021-12-28	criteria provided, single submitter	clinical testing
Ambry Genetics	RCV002354195	SCV002653355	pathogenic	Cardiovascular phenotype	2023-03-29	criteria provided, single submitter	clinical testing	The c.1211dupT pathogenic mutation, located in coding exon 5 of the PKP2 gene, results from a duplication of T at nucleotide position 1211, causing a translational frameshift with a predicted alternate stop codon (p.V406Sfs*4). This alteration has been reported in subjects with arrhythmogenic right ventricular cardiomyopathy (ARVC) (van Tintelen JP et al. Circulation, 2006 Apr;113:1650-8; Xu T et al. J. Am. Coll. Cardiol., 2010 Feb;55:587-97; Walsh R et al. Genet. Med., 2017 02;19:192-203). This variant is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). In addition to the clinical data presented in the literature, this alteration is expected to result in loss of function by premature protein truncation or nonsense-mediated mRNA decay. As such, this alteration is interpreted as a disease-causing mutation.
CeGaT Center for Human Genetics Tuebingen	RCV001699188	SCV002821690	pathogenic	not provided	2022-11-01	criteria provided, single submitter	clinical testing	PKP2: PVS1, PM2
Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	RCV000603676	SCV000733163	pathogenic	Arrhythmogenic right ventricular dysplasia 9		no assertion criteria provided	clinical testing
Clinical Genetics, Academic Medical Center	RCV001699188	SCV001918289	pathogenic	not provided		no assertion criteria provided	clinical testing
Genome Diagnostics Laboratory, University Medical Center Utrecht	RCV001699188	SCV001926794	pathogenic	not provided		no assertion criteria provided	clinical testing
Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	RCV001699188	SCV001958211	pathogenic	not provided		no assertion criteria provided	clinical testing