ClinVar Miner

Submissions for variant NM_004572.3(PKP2):c.2554del (p.Glu852fs) (rs1353074803)

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Total submissions: 2
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Invitae RCV000541578 SCV000638892 pathogenic Arrhythmogenic right ventricular cardiomyopathy, type 9 2017-06-29 criteria provided, single submitter clinical testing This sequence change results in a premature translational stop signal in the PKP2 gene (p.Glu852Asnfs*79). While this is not anticipated to result in nonsense mediated decay, it is expected to disrupt the last 29 amino acids of the PKP2 protein. This variant is not present in population databases (ExAC no frequency). This variant has been reported in multiple unrelated individuals affected with arrhythmogenic right ventricular cardiomyopathy (PMID: 19427443, 24125834, Invitae). For these reasons, this variant has been classified as Pathogenic.
Stanford Center for Inherited Cardiovascular Disease, Stanford University RCV000786186 SCV000924894 likely pathogenic not provided 2017-07-31 no assertion criteria provided provider interpretation Testing for our patient was performed at the Invitae laboratory and may overlap with any case data. Given the type of variant, the rarity, and the case data, we consider this variant likely pathogenic and we do feel it is suitable for assessing risk in healthy relatives ("predictive genetic testing"). It is notable that the variant has only reported in Chinese individuals. The variant has been seen in at least 4, possibly 5, unrelated cases of ARVC (not including this patient's family). Qiu et al (2009) observed the variant in 3 of 18 unrelated Chinese patients with ARVC who undwerwent sequencing of just PKP2. THey did not report haplotype or other analyses to determine if these individuals had a common ancestor. Subjects were enrolled in a Chinese national ARVC registry. Bao et al (2013) observed this variant in their Chinese cohort as well, with no details available about how the cohort was recruited (hard to ascertain any overlap with Qiu et al). Multiple ARVC genes were sequenced. It is unclear how many patients the variant was seen in. Invitae notes they have also seen this variant in ARVC cases. Baskin et al (2013) observed the variant in 1 of 195 individuals in a Canadian cohort with suspected ARVC. Ancestry was not reported. The lab report also indicates that the variant has been seen in other individuals with ARVC at Invitae, but when I called to follow up on that, they said our patient was the patient that they were referring to. It is not listed in ClinVar. It is not listed in http://www.arvcdatabase.info/. There is another truncating variant at the neighboring amino acid, listed as likely pathogenic by LMM. In their ClinVar entry for that variant they speak to the possible protein effect: "Heterozygous loss of PKP2 function is an established disease mechanism for ARVC; however it is unclear how the p.Thr851fsExtX50 variant would impact the protein function. Of note, 4 other variants having a similar impact to the protein (p.Ser837fsExtX50, p.Leu847fsExtX50, p.Glu852fsExtX50, p.Lys859fsExtX50) have been described in >15 individuals with ARVC (Gerull 2004, Antoniades 2006, Dalal 2006, Asimaki 2009, Dalal 2009, Fressart 2010, Den Haan 2009, Watkins 2009, Qiu 2009, Xu 2010, Barahona-Dussault 2010, Tan, 2010, Cox 2011, Baskin 2013, Alcalde 2014), suggesting that PKP2 protein extension variants are disease-causing." The lab report notes "while this is not anticipated to result in nonsense mediated decay, it is expected to disrupt the last 29 amino acids of the PKP2 protein." The variant was reported online in 1 of 123108 individuals in the Genome Aggregation Consortium Dataset (gnomAD; http://gnomad.broadinstitute.org/), which currently includes variant calls on >140,000 unrelated individuals of African, Asian, European, Ashkenazi, Latino descent. Specifically, the variant was observed in 1 of 8624 individuals of East Asian descent (MAF=0.0058%). The phenotype of those individuals is not publicly available. The dataset is comprised of multiple cohorts, some of which were recruited from the general population, others were enriched for common cardiovascular disease.

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