Submissions for variant NM_001005242.3(PKP2):c.1252del (p.Ala418fs)

dbSNP: rs1555145509

Total submissions: 2

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Labcorp Genetics (formerly Invitae), Labcorp	RCV000551855	SCV000638861	pathogenic	Arrhythmogenic right ventricular dysplasia 9	2018-07-06	criteria provided, single submitter	clinical testing	This sequence change deletes 1 nucleotide from exon 5 of the PKP2 mRNA (c.1252delG), causing a frameshift at codon 418. This creates a premature translational stop signal (p.Ala418Profs*2) 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.
GeneDx	RCV000627451	SCV000748451	likely pathogenic	not provided	2018-01-29	criteria provided, single submitter	clinical testing	Although the c.1252delG likely pathogenic variant in the PKP2 gene has not been reported to our knowledge, this variant causes a shift in reading frame starting at codon alanine 418, changing it to a proline, and creating a premature stop codon at position 2 of the new reading frame, denoted p.Ala418ProfsX2. This variant is expected to result in either an abnormal, truncated protein product or loss of protein from this allele through nonsense-mediated mRNA decay. Multiple other downstream frameshift variants in the PKP2 gene have been reported in Human Gene Mutation Database in association with ARVC (Stenson et al., 2014), indicating that loss of function is a mechanism of disease for this gene. Furthermore, the c.1252delG variant has not been observed in large population cohorts (Lek et al., 2016).Therefore, this variant is likely pathogenic. The presence of this variant indicates that this individual is likely at increased risk to develop arrhythmia.