PKP2 D26N - GET-Evidence



(PKP2 Asp26Asn)

Short summary

Probably benign. This variant has been classified as a rare polymorphism, although other variants in this gene have been implicated in causing autosomal dominant arrhythmogenic right ventricular dysplasia (which can cause sudden death at an early age).

Variant evidence
Computational 2

Position not conserved, BLOSUM100 indicates Asp to Asn substitution is not usually disruptive.

Functional -
Case/Control 5

Findings in controls is strongly significant deviation from severe pathogenic effect.

See Klauke B et al. 2010 (20829228).

Familial -
Clinical importance
Severity -
Treatability -
Penetrance -


Low clinical importance, Likely benign

(The "low clinical importance, likely" qualifier is assigned automatically based on the above evidence and importance scores.)

Inheritance pattern


Summary of published research, and additional commentary

van Tintelen et al. were unsure as to the pathogenicity of this variant. Later findings from Klauke et al. and other papers found this variant present, at a similiarly low frequency, in controls. Because of this, and because the variant is not conserved and is not predicted to be disruptive, it is classified as benign.

The findings of Klauke et al. in controls strongly contradicts a severe pathogenic effect for this variant, even for a pathogenic hypothesis that is quite generous. Assuming ARVD has a prevalence of 1 in 1000, that mutations in PKP2 account for 40% of disease, that the hypothetical pathogenic variant accounts for 20% of PKP2-attributable disease, and the variant has a penetrance of just 4% — such a variant would be predicted to have an allele frequency of .2% — 10 out of 726 randomly chosen chromosomes having the variant deviates from this frequency with a significance 3 * 10^-6.

Total cases/controls case+ case– control+ control– p-value odds ratio
Arrhythmogenic Right Ventricular Dysplasia/Cardiomyopathy, Autos
1 21 10 353 0.4811 1.681


Allele frequency

  • T @ chr12:33049590: 0.5% (50/10296) in EVS
  • T @ chr12:32940856: 0.9% (1/108) in GET-Evidence
  • Frequency shown in summary reports: 0.5% (50/10296)


van Tintelen JP, Entius MM, Bhuiyan ZA, Jongbloed R, Wiesfeld AC, Wilde AA, van der Smagt J, Boven LG, Mannens MM, van Langen IM, Hofstra RM, Otterspoor LC, Doevendans PA, Rodriguez LM, van Gelder IC, Hauer RN. Plakophilin-2 mutations are the major determinant of familial arrhythmogenic right ventricular dysplasia/cardiomyopathy. Circulation. 2006 Apr 4;113(13):1650-8. Epub 2006 Mar 27. PubMed PMID: 16567567.

This variant was implicated in autosomal dominant Arrhythmogenic right ventricular dysplasia, but was “unclassified pathogenicity” due to (1) it not being in a conserved region and (2) predicted not very deleterious.

Klauke B, Kossmann S, Gaertner A, Brand K, Stork I, Brodehl A, Dieding M, Walhorn V, Anselmetti D, Gerdes D, Bohms B, Schulz U, Zu Knyphausen E, Vorgerd M, Gummert J, Milting H. De novo desmin-mutation N116S is associated with arrhythmogenic right ventricular cardiomyopathy. Hum Mol Genet. 2010 Dec 1;19(23):4595-607. Epub 2010 Sep 9. PubMed PMID: 20829228.

This variant was seen in 1 out of 22 patients and 10 out of 363 blood donors (randomly selected controls), the authors conclude it is a polymorphism.

Cases/controls case+ case– control+ control– p-value odds ratio
Arrhythmogenic Right Ventricular Dysplasia/Cardiomyopathy, Autos
1 21 10 353 0.4811 1.681



huE80E3D - CGI sample GS00253-DNA_D01_200_37
het T @ chr12:33049590


Other external references

  • GeneTests records for the PKP2 gene
    Arrhythmogenic Right Ventricular Dysplasia/Cardiomyopathy, Autos
    Arrhythmogenic Right Ventricular Dysplasia/Cardiomyopathy 9

Other in silico analyses

  • NBLOSUM100 score = –1
  • GET-Evidence autoscore = 4

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Gene search

"GENE" or "GENE A123C":

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