ClinVar Miner

Submissions for variant NM_004572.3(PKP2):c.533dup (p.His179fs) (rs769220833)

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Total submissions: 3
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000183782 SCV000236263 pathogenic not provided 2013-05-29 criteria provided, single submitter clinical testing c.533dupT: p.His179AlafsX37 (H179AfsX37) in exon 3 of the PKP2 gene (NM_004572.3). The normal sequence with the base that is inserted in braces is: ACCC{T}GCAC. Although the c.533dupT mutation in the PKP2 gene has not been reported to our knowledge, this mutation causes a shift in reading frame starting at codon Histidine 179, changing it to an Alanine, and creating a premature stop codon at position 37 of the new reading frame, denoted p.His179AlafsX37. This mutation is expected to result in either an abnormal, truncated protein product or loss of protein from this allele through nonsense-mediated mRNA decay. Other frameshift mutations in the PKP2 gene have been reported in association with ARVC. The c.533dupT mutation in the PKP2 gene also has been observed in one other unrelated individuals at GeneDx. In summary, c.533dupT in the PKP2 gene is interpreted as a disease-causing mutation. Arrhythmogenic right ventricular cardiomyopathy (ARVC) is primarily an autosomal dominant disease characterized by progressive fibrofatty replacement of the myocardium that predisposes to ventricular tachycardia and sudden death (McNally E et al., 2009; Nava A et al., 2000). ARVC is most frequently caused by mutations in the genes encoding desmosomal proteins, complexes that maintain cell-to-cell connections and provide mechanical attachments among adjacent cells. Less commonly, ARVC may be caused by mutations in genes that encode proteins that maintain calcium homeostasis (McNally E et al., 2009). At least 11% of patients with autosomal dominant arrhythmogenic right ventricular cardiomyopathy were reported to have a mutation in the PKP2 gene (McNally E et al., 2009). The variant is found in ARVC panel(s).
Laboratory for Molecular Medicine, Partners HealthCare Personalized Medicine RCV000600205 SCV000713178 likely pathogenic Arrhythmogenic right ventricular cardiomyopathy 2017-07-27 criteria provided, single submitter clinical testing The p.His179fs variant in PKP2 has not been previously reported in the literatur e, but has been reported in ClinVar (Variation ID: 202012). This variant has als o been identified in 1/15302 African chromosomes by the Genome Aggregation Datab ase (gnomAD,; dbSNP rs769220833). This variant is predicted to cause a frameshift, which alters the protein?s amino acid sequen ce beginning at position 179 and leads to a premature termination codon 37 amino acids downstream. This alteration is then predicted to lead to a truncated or a bsent protein. Frameshift and other truncating variants in PKP2 are well-reporte d in individuals with ARVC (ARVD/C Genetic Variant Database, http://arvcdatabase .info; Human Gene Mutation Database). In summary, although additional studies ar e required to fully establish its clinical significance, the p.His179fs variant is likely pathogenic.
Invitae RCV000794490 SCV000933902 pathogenic Arrhythmogenic right ventricular cardiomyopathy, type 9 2019-10-28 criteria provided, single submitter clinical testing This sequence change creates a premature translational stop signal (p.His179Alafs*37) in the PKP2 gene. It is expected to result in an absent or disrupted protein product. The frequency data for this variant in the population databases is considered unreliable, as metrics indicate poor data quality at this position in the ExAC database. This variant has not been reported in the literature in individuals with PKP2-related disease. ClinVar contains an entry for this variant (Variation ID: 202012). Loss-of-function variants in PKP2 are known to be pathogenic (PMID: 15489853, 23911551). For these reasons, this variant has been classified as Pathogenic.

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