Submissions for variant NM_001005242.3(PKP2):c.1379-2047_1379-2043del

dbSNP: rs775995156

Total submissions: 6

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000483764	SCV000568236	likely pathogenic	not provided	2017-07-12	criteria provided, single submitter	clinical testing	This five base pair deletion has been reported previously in the Human Gene Mutation Database and the Arrhythmogenic Right Ventricular Cardiomyopathy database (Stenson et al., 2014; Van et al., 2009). The c.1440_1444delTCCCA variant was not observed in approximately 6,500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, indicating it is not a common benign variant in these populations. This variant causes a shift in reading frame starting at codon Asparagine 480, changing it to a Lysine, and creating a premature stop codon at position 20 of the new reading frame, denoted p.Asn480LysfsX20. 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).
Invitae	RCV001069896	SCV001235094	pathogenic	Arrhythmogenic right ventricular dysplasia 9	2022-11-01	criteria provided, single submitter	clinical testing	This variant is present in population databases (rs775995156, gnomAD 0.002%). This sequence change creates a premature translational stop signal (p.Asn480Lysfs*20) 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, 23911551). This premature translational stop signal has been observed in individual(s) with arrhythmogenic right ventricular cardiomyopathy (PMID: 25157032). For these reasons, this variant has been classified as Pathogenic. ClinVar contains an entry for this variant (Variation ID: 419977).
Color Diagnostics, LLC DBA Color Health	RCV001184322	SCV001350273	uncertain significance	Cardiomyopathy	2022-12-02	criteria provided, single submitter	clinical testing	This variant deletes 5 nucleotides in exon 6 of the PKP2b transcript (ENST00000070846 | NM_004572), creating a frameshift and premature translation stop signal. This exon 6 is alternately spliced out and is absent in the PKP2a transcript, the predominant isoform in the heart (ENST00000340811 | NM_001005242, PMID 21378009). Therefore, it is likely that a functional PKP2 gene product is expressed in the heart, despite the presence of this variant. To our knowledge, functional studies have not been reported for this variant. This variant has been reported in three individuals affected with arrhythmogenic right ventricular cardiomyopathy, including two from the same family who also carried a pathogenic variant in the DSP gene (PMID: 25157032, 28588093). This variant has been identified in 3/271396 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.
Baylor Genetics	RCV001069896	SCV004041413	likely pathogenic	Arrhythmogenic right ventricular dysplasia 9	2023-02-28	criteria provided, single submitter	clinical testing
Gharavi Laboratory, Columbia University	RCV000483764	SCV000809447	pathogenic	not provided	2018-09-16	no assertion criteria provided	research
Cardiology unit, Meyer University Hospital	RCV001069896	SCV002577350	likely pathogenic	Arrhythmogenic right ventricular dysplasia 9	2022-09-27	no assertion criteria provided	clinical testing