ClinVar Miner

Submissions for variant NM_001005242.3(PKP2):c.2352C>T (p.Gly784=) (rs727504509)

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Total submissions: 6
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Laboratory for Molecular Medicine, Partners HealthCare 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 2020-05-19 criteria provided, single submitter clinical testing Not observed at a significant frequency in large population cohorts (Lek et al., 2016); 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)
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 Clinical Services Laboratory,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 Health, Inc RCV001189967 SCV001357368 uncertain significance Cardiomyopathy 2021-02-01 criteria provided, single submitter clinical testing This synonymous variant does not change the amino acid sequence of the PKP2 protein. Splice site prediction tools suggest that this variant may 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 an individual affected with arrhythmogenic right ventricular cardiomyopathy (ARVC) (PMID: 17041889). The proband's three heterozygous, teenaged children were unaffected. This and other studies (PMID: 19358943, 20031617, 20857253, 23671136, 23810883, 23810894) that have reported this variant in individuals affected with, or suspected of having, ARVC describe the study population drawn from the Johns Hopkins ARVC Registry. 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 disease, 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.
Invitae RCV001115020 SCV001393330 uncertain significance Arrhythmogenic right ventricular dysplasia 9 2020-01-22 criteria provided, single submitter clinical testing 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. This variant is present in population databases (rs727504509, ExAC 0.003%). This variant has been observed as homozygous in an individual with arrhythmogenic right ventricular cardiomyopathy (ARVC) (PMID: 17041889). This variant has also been observed as homozygous in an asymptomatic individual with ECG abnormalities (PMID: 23810883). ClinVar contains an entry for this variant (Variation ID: 178879). Experimental studies have shown that this variant disrupts mRNA splicing (PMID: 17041889, 23354045). In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance.

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