ClinVar Miner

Submissions for variant NM_001005242.3(PKP2):c.2108del (p.Lys703fs) (rs1565574709)

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Total submissions: 1
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Stanford Center for Inherited Cardiovascular Disease, Stanford University RCV000786187 SCV000924895 likely pathogenic not provided 2016-11-16 no assertion criteria provided provider interpretation Given the absence in controls and the variant type we consider this variant likely disease causing (aka likely pathogenic) and we do feel it is suitable for assessing risk in healthy relatives ("predictive genetic testing"). This variant is absent in ClinVar (as of 11/16/2016), but other frameshift variants are reported as likely pathogenic or pathogenic. The variant has been seen in at least one unrelated cases of ARVC (not including our patient's family). No segregation studies available. Bao et al. (2013) reports one patient with ARVC who was found to have this variant, at the time novel. The study population comprised Chinese patients with either a definite, borderline, or possible diagnosis of ARVC. All participants had ventricular arrhythmias recorded, but no specific phenotypic individual for that patient was available. No segregation was included in this report. This variant is in exon 11. It creates a frameshift beginning with codon Lysine 747, changing this to an Arginine and creating a premature stop codon at position 7 of the new reading frame. It is expected to result in an abnormal, truncated protein. At least two dozen splice variants in this gene have been reported in association with ARVC (see http://www.arvcdatabase.info/). The majority of the disease-associated variants in PKP2 are splicing variants, frameshift, nonsense, or in-frame deletions. In one study 66 of 149 unrelated ARVC patients had such a variant (Cox et al 2011). In contrast, these variants are rare in the general population (Kapplinger et al 2011, ExAC, gnomAD). A study by Amr et al (2016) also supports the assumption that the PKP2 gene is intolerant to loss of function variation, reporting loss of function variants enriched in cases vs controls (OR: 114). There is no variation at codon 747 listed in the Genome Aggregation Consortium Dataset (gnomAD; http://gnomad.broadinstitute.org/), which currently includes variant calls on >140,000 unrelated individuals of African, Asian (9,472 East Asian individuals in particular), European, Latino, and Ashkenazi descent. The average coverage at that site in gnomAD is 90x

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