Submissions for variant NM_001005242.3(PKP2):c.2352C>T (p.Gly784=)

gnomAD frequency: 0.00004  dbSNP: rs727504509

Total submissions: 9

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	RCV000155651	SCV000205360	uncertain significance	not specified	2019-01-30	criteria provided, single submitter	clinical testing	Variant classified as Uncertain Significance - Favor Pathogenic. The p.Gly828Gly variant in PKP2 has been reported as homozygous in 1 adult with ARVC and as heterozygous in her unaffected parents (Awad 2006, Dalal 2009, den Haan 2009, Tan 2010) and as homozygous in 1 asymptomatic teenager with RBBB and other abnormal EKG findings (Perrin 2013). It was also identified in 2/66738 European chromosomes by the Exome Aggregation Consortium (ExAC; http://exac.broadinstitute.org/; dbSNP rs727504509). mRNA studies showed that the 2484C>T variant results in a 7 bp deletion at the end of exon 12, resulting in a frameshift that extends the coding sequence by 145 bp (48 amino acids; Awad 2006, Kim 2013). While it is unclear if this variant would be disease-causing in isolation, the available evidence suggests that it is likely pathogenic when seen in homozygosity or with a second PKP2 variant. However, additional studies are needed to fully assess the clinical significance of this variant.
GeneDx	RCV000183713	SCV000236191	uncertain significance	not provided	2022-09-02	criteria provided, single submitter	clinical testing	Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports a deleterious effect on splicing; Identified in isolation and in conjunction with additional cardiogenetic variants in individuals in the literature, but segregation data are limited or absent at this time (Ali et al., 2018; Dalal et al., 2009); Identified in at least two patients in the literature with ARVC who were homozygous for c.2484 C>T and heterozygous relatives were reported to be unaffected or asymptomatic (Awad et al., 2006; Tan et al., 2010; den Haan et al., 2009); This variant is associated with the following publications: (PMID: 23810883, 28573431, 17041889, 23354045, 29961461, 20857253, 20031617, 30205876, 19358943, 27030002, 31402444, 32180835, 33206225, 33595719, 35059364, 31963859, 33802229, 34079803, 33536939, 28329361, 23671136, 24352520, 24632794)
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	RCV000183713	SCV000885970	likely pathogenic	not provided	2017-08-18	criteria provided, single submitter	clinical testing	In a homozygous state, the c.2484C>T variant (rs727504509) has been reported in the medical literature in two individuals with arrhythmogenic right ventricular dysplasia (Awad 2006, Dalal 2009, den Haan 2009, and Tan 2010) as well as an asymptomatic teenager with abnormal EKG findings (Perrin 2013). Individuals who were heterozygous for the variant were unaffected (Awad 2006). Functional evidence indicates that the c.2484C>T variant creates a cryptic splice site that causes a frame shift, which disrupts the last 54 amino acids, adds an additional 48 residues, and alters protein localization and function (Awad 2006 and Kim 2013). The c.2484C>T variant is listed in the Genome Aggregation Database (gnomAD) browser with a frequency of 0.0036% in non-Finnish Europeans (identified in 4 out of 111,662 chromosomes) and is listed the ClinVar database with conflicting interpretations of pathogenicity (variant of uncertain significance/likely pathogenic; Variation ID: 178879). Based on the available evidence, the c.2484C>T variant is likely to be pathogenic. Pathogenic variants in PKP2 are typically inherited in an autosomal dominant manner and are associated with arrhythmogenic right ventricular dysplasia 9 (MIM: 609040). Because the c.2484C>T variant is reported to be associated with autosomal recessive arrhythmogenic right ventricular dysplasia, it is unlikely that this variant is responsible for the patient’s phenotype; however, a modifying role cannot be ruled out.
Illumina Laboratory Services, Illumina	RCV001115020	SCV001272952	uncertain significance	Arrhythmogenic right ventricular dysplasia 9	2017-04-28	criteria provided, single submitter	clinical testing	This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). Publications were found based on this search. However, the evidence from the literature, in combination with allele frequency data from public databases where available, was not sufficient to rule this variant in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance.
Color Diagnostics, LLC DBA Color Health	RCV001189967	SCV001357368	uncertain significance	Cardiomyopathy	2023-06-22	criteria provided, single submitter	clinical testing	This synonymous variant in the PKP2 protein is predicted to impact RNA splicing by creating a new splice donor site 7 nucleotides upstream from the native donor site. A functional RNA study in cells derived from a homozygous individual has shown that this variant causes aberrant splicing and deletion of the last 7 nucleotides in exon 12 (PMID: 17041889). The ensuing frameshift is expected to disrupt the last 54 amino acids of PKP2 protein and extend the C-terminus by 48 amino acids. This variant has been reported in homozygosity in two unrelated individuals affected with arrhythmogenic right ventricular cardiomyopathy (ARVC) (PMID: 17041889, 29961461). One of the proband's three heterozygous, teenaged children were unaffected. This variant has been observed in multiple individuals from the same cohort (PMID: 19358943, 20031617, 20857253, 23671136, 23810883, 23810894) and it is not clear how many unrelated, affected individuals are known to carry this variant. This variant has been identified in 5/282794 chromosomes in the general population by the Genome Aggregation Database (gnomAD). Although there is a suspicion that this variant may be associated with autosomal recessive ARVC, the available evidence is insufficient to determine the role of this variant in autosomal dominant ARVC conclusively. Therefore, this variant is classified as a Variant of Uncertain Significance.
Labcorp Genetics (formerly Invitae), Labcorp	RCV001115020	SCV001393330	likely pathogenic	Arrhythmogenic right ventricular dysplasia 9	2023-07-12	criteria provided, single submitter	clinical testing	In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic. Studies have shown that this variant results in partial skipping of exon 12 and introduces a new termination codon (PMID: 17041889). However the mRNA is not expected to undergo nonsense-mediated decay. ClinVar contains an entry for this variant (Variation ID: 178879). This variant has been observed in individuals with arrhythmogenic right ventricular cardiomyopathy or clinical features of this condition in the homozygous state (PMID: 17041889, 23810883, 29961461). This variant is present in population databases (rs727504509, gnomAD 0.004%). This sequence change affects codon 828 of the PKP2 mRNA. It is a 'silent' change, meaning that it does not change the encoded amino acid sequence of the PKP2 protein. RNA analysis indicates that this variant induces altered splicing and likely disrupts the C-terminus of the protein.
Ambry Genetics	RCV002426750	SCV002743678	likely pathogenic	Cardiovascular phenotype	2023-12-27	criteria provided, single submitter	clinical testing	The c.2484C>T variant (also known as p.G828G), located in coding exon 12 of the PKP2 gene, results from a C to T substitution at nucleotide position 2484. This nucleotide substitution does not change the glycine at codon 828. This variant has been reported in the homozygous state in individuals with arrhythmogenic right ventricular cardiomyopathy (ARVC); however, it has also been reported in an asymptomatic homozygote, as well as in unaffected heterozygotes (Awad MM et al. Hum. Mutat., 2006 Nov;27:1157; den Haan AD et al. Circ Cardiovasc Genet, 2009 Oct;2:428-35;Perrin MJ et al. J Am Coll Cardiol, 2013 Nov;62:1772-9; Ali M et al. Indian Heart J 2018 Oct;70:421-426). This nucleotide position is not well conserved in available vertebrate species. In silico splice site analysis predicts that this alteration will result in the creation or strengthening of a novel splice donor site. RNA studies demonstrated splicing impact in the majority of transcripts derived from the variant allele (Awad MM et al. Hum. Mutat., 2006 Nov;27:1157; Kim C et al. Nature, 2013 Feb;494:105-10). Based on the supporting evidence, this variant is likely to be pathogenic for arrhythmogenic right ventricular cardiomyopathy (ARVC) when present along with a second pathogenic variant on the other allele; however, its clinical significance in the heterozygous state is unclear.
CeGaT Center for Human Genetics Tuebingen	RCV000183713	SCV004130534	uncertain significance	not provided	2022-10-01	criteria provided, single submitter	clinical testing	PKP2: PM2:Supporting, PP3
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV004767095	SCV005380346	pathogenic	Familial isolated arrhythmogenic right ventricular dysplasia	2024-08-22	criteria provided, single submitter	clinical testing	Variant summary: PKP2 c.2484C>T alters a non-conserved nucleotide resulting in a synonymous change. Several computational tools predict a significant impact on normal splicing: Four predict the variant creates a 5' donor site. At least one publication reports experimental evidence that this variant creates a cryptic splice site and introduces a premature termination codon (Awad_2006). The variant allele was found at a frequency of 1.6e-05 in 251434 control chromosomes. c.2484C>T has been reported in the literature in the homozygous and compound heterozygous states in individuals affected with Arrhythmogenic Right Ventricular Dysplasia (ARVD)/Cardiomyopathy (Awad_2006, Bhonsale_2013, Janin_2022, Ali_2018) and homozygous in at least one asymptomatic individual with abnormal EEG findings (Perrin_2013). Heterozygous individuals have been reported as unaffected (e.g. Awad_2006, Yang_2022). These data indicate that the variant is likely to be associated with autosomal recessive disease. At least one experimental study using iPSC cardiomyocyte cell lines homozygous for this variant showed that these cells exhibit characteristics of Arrhythmogenic Right Ventricular Dysplasia (e.g. Wen_2015). The following publications have been ascertained in the context of this evaluation (PMID: 29961461, 17041889, 23671136, 35838873, 23810883, 25971409, 36129056). ClinVar contains an entry for this variant (Variation ID: 178879). To our knowledge, this variant has not been reported in patients with autosomal dominant ARVD. Based on the evidence outlined above, this variant is pathogenic for autosomal recessive ARVD.