Submissions for variant NM_001005242.3(PKP2):c.68del (p.Gly23fs)

dbSNP: rs1555149975

Total submissions: 3

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Labcorp Genetics (formerly Invitae), Labcorp	RCV000525388	SCV000638905	pathogenic	Arrhythmogenic right ventricular dysplasia 9	2019-06-11	criteria provided, single submitter	clinical testing	For these reasons, this variant has been classified as Pathogenic. While this particular variant has not been reported in the literature, loss-of-function variants in PKP2 are known to be pathogenic (PMID: 15489853). 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.
Ambry Genetics	RCV004984961	SCV005476559	pathogenic	Cardiovascular phenotype	2024-10-02	criteria provided, single submitter	clinical testing	The c.68delG pathogenic mutation, located in coding exon 1 of the PKP2 gene, results from a deletion of one nucleotide at nucleotide position 68, causing a translational frameshift with a predicted alternate stop codon (p.G23Dfs*16). This variant is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). This alteration is expected to result in loss of function by premature protein truncation or nonsense-mediated mRNA decay. As such, this alteration is interpreted as a disease-causing mutation.
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.