ClinVar Miner

Submissions for variant NM_004572.3(PKP2):c.68del (p.Gly23fs) (rs1555149975)

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Total submissions: 2
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Invitae RCV000525388 SCV000638905 pathogenic Arrhythmogenic right ventricular cardiomyopathy, type 9 2019-06-13 criteria provided, single submitter clinical testing This sequence change deletes 1 nucleotide from exon 1 of the PKP2 mRNA (c.68delG), causing a frameshift at codon 23. This creates a premature translational stop signal (p.Gly23Aspfs*16) and is expected to result in an absent or disrupted protein product. While this particular variant has not been reported in the literature, loss-of-function variants in PKP2 are known to be pathogenic (PMID: 15489853). For these reasons, this variant has been classified as Pathogenic.
Stanford Center for Inherited Cardiovascular Disease, Stanford University RCV000786188 SCV000924896 pathogenic not provided 2017-04-11 no assertion criteria provided provider interpretation Given that loss of function variation is a known mechanism of disease in PKP2 and its absence from large population databases, we consider this variant disease-causing and we do feel it is suitable for assessing risk in healthy relatives ("predictive genetic testing"). This particular variant appears novel. It has not been reported in the literature and is not present in ClinVar. However, loss of function variation is a known mechanism of disease in PKP2. 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, NHLBI ESP). 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 23 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, European, Latino, and Ashkenazi descent. The average coverage at that site in gnomAD is 31x.

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