Submissions for variant NM_001005242.3(PKP2):c.1689dup (p.Val564fs)

dbSNP: rs397517010

Total submissions: 8

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	RCV000038187	SCV000061854	likely pathogenic	Arrhythmogenic right ventricular cardiomyopathy	2018-02-20	criteria provided, single submitter	clinical testing	The p.Val608fs variant in PKP2 has been reported in 2 individuals with clinical features of ARVC (Bhonsale 2013, LMM unpublished data). This variant has been id entified in 1/111470 of European chromosomes by the Genome Aggregation Database (gnomAD, http://gnomad.broadinstitute.org; dbSNP rs397517010) and has been previ ously reported in ClinVar (Variation ID 45047). This variant is predicted to cau se a frameshift, which alters the protein?s amino acid sequence beginning at pos ition 608 and leads to a premature termination codon 6 amino acids downstream. T his alteration is then predicted to lead to a truncated or absent protein. Heter ozygous loss of function of the PKP2 gene is an established disease mechanism in ARVC. In summary, although additional studies are required to fully establish i ts clinical significance, the p.Val608fs variant is likely pathogenic. ACMG/AMP Criteria applied: PVS1; PM2; PS4_S (Richards 2015).
Ambry Genetics	RCV000242219	SCV000320675	pathogenic	Cardiovascular phenotype	2016-01-02	criteria provided, single submitter	clinical testing	The c.1821dupT pathogenic mutation, located in coding exon 9 of the PKP2 gene, results from a duplication of T at nucleotide position 1821, causing a translational frameshift with a predicted alternate stop codon (p.V608Cfs*6). This alteration has been reported in patients with arrhythmogenic right ventricular dysplasia/cardiomyopathy (ARVD/C) (Bhonsale A et al. Circ Arrhythm Electrophysiol. 2013;6(3):569-78; Bhonsale A et al. Eur Heart J. 2015;36(14):847-55; Groeneweg JA et al. Circ Cardiovasc Genet. 2015;8(3):437-46; te Riele AS et al. JACC: Clinical Electrophysiology. 2015;1(6):551-60). In addition to the clinical data presented in the literature, since frameshifts are typically deleterious in nature, this alteration is interpreted as a disease-causing mutation (ACMG Recommendations for Standards for Interpretation and Reporting of Sequence Variations. Revision 2007. Genet Med. 2008;10:294).
Labcorp Genetics (formerly Invitae), Labcorp	RCV000640015	SCV000761602	pathogenic	Arrhythmogenic right ventricular dysplasia 9	2021-08-03	criteria provided, single submitter	clinical testing	For these reasons, this variant has been classified as Pathogenic. Loss-of-function variants in PKP2 are known to be pathogenic (PMID: 15489853, 23911551). This variant has been reported in individuals affected with arrhythmogenic right ventricular cardiomyopathy (PMID: 28588093, Invitae). ClinVar contains an entry for this variant (Variation ID: 45047). This variant is present in population databases (rs397517010, ExAC 0.001%). This sequence change creates a premature translational stop signal (p.Val608Cysfs*6) in the PKP2 gene. It is expected to result in an absent or disrupted protein product.
Human Genome Sequencing Center Clinical Lab, Baylor College of Medicine	RCV000640015	SCV000840043	likely pathogenic	Arrhythmogenic right ventricular dysplasia 9	2018-04-25	criteria provided, single submitter	clinical testing	This c.1821_1822insT (p.Val608Cysfs*6) variant in the PKP2 gene has not been reported previously while observed with extremely low allele frequency in general population according to gnomad database. This variant is predicted to cause loss of function of normal protein through mRNA decay or producing a truncated protein, which is a known disease mechanism for this gene. Based on current evidences, this c.1821_1822insT (p.Val608Cysfs*6) variant in the PKP2 gene is classified as likely pathogenic.
GeneDx	RCV001008767	SCV001168555	pathogenic	not provided	2022-09-22	criteria provided, single submitter	clinical testing	Frameshift variant predicted to result in protein truncation or nonsense mediated decay in a gene for which loss-of-function is a known mechanism of disease; Not observed at significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 25616645, 34120153, 23671136, 26314686, 25820315, 28588093, 31402444, 31447099, 31386562, 35536239, 31319917)
CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario	RCV001171163	SCV001333848	likely pathogenic	Cardiomyopathy	2019-03-14	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV002265578	SCV002548331	pathogenic	Familial isolated arrhythmogenic right ventricular dysplasia	2022-05-31	criteria provided, single submitter	clinical testing	Variant summary: PKP2 c.1821dupT (p.Val608CysfsX6) results in a premature termination codon, predicted to cause a truncation of the encoded protein or absence of the 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. The variant allele was found at a frequency of 4e-06 in 251212 control chromosomes. c.1821dupT has been reported in the literature in individuals affected with Arrhythmogenic Right Ventricular Dysplasia/Cardiomyopathy (example, Bhonsale_2013, te Riele_2016, DeWitt_2020). These data indicate that the variant is likely to be associated with disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Six 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 pathogenic/likely pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic.
Molecular Genetics, Royal Melbourne Hospital	RCV000038187	SCV004812561	pathogenic	Arrhythmogenic right ventricular cardiomyopathy	2024-03-01	criteria provided, single submitter	clinical testing	This sequence change in PKP2 is a frameshift variant predicted to cause a premature stop codon, p.(Val564Cysfs*6), in biologically relevant exon 8/14 leading to nonsense-mediated decay in a gene in which loss of function is an established disease mechanism. The highest population minor allele frequency in the population database gnomAD v4.0 is 0.0009% (10/1,111,944 alleles) in the European (non-Finnish) population. This variant has been reported in at least four unrelated probands with a clinical diagnosis of arrhythmogenic right ventricular cardiomyopathy and segregates with disease in at least two families (PMID: 31319917, 28588093, 34469894). Based on the classification scheme RMH Modified ACMG/AMP Guidelines v1.6.1, this variant is classified as PATHOGENIC. Following criteria are met: PVS1, PM2_Supporting, PP1, PS4_Supporting