PKP2 S140F - GET-Evidence


PKP2 S140F

(PKP2 Ser140Phe)

Short summary

Implicated as causing Arrhythmogenic Right Ventricular Dysplasia/Cardiomyopathy in a dominant manner. However, it fails to segregate with disease in studied families and has also been seen in controls. It is unclear whether there is any significant enrichment for this variant in patients — even if so, we estimate the increased risk of ARVD for a carrier of this variant to be quite low (less than .1%).

Variant evidence
Computational -1

Both Polyphen and Sift find this variant to be benign. The variant is also poorly conserved.

See 19955750, den Haan AD et al. 2009 (20031617).

Case/Control 2

P = 0.046

Familial -1

Christensen et al. report two families carrying the S140F mutation did not show a genotype-phenotype correlation. Syrris et al. also report an affected non-carrier in the family they studied.

See Syrris P et al. 2006 (16415378), 19955750.

Clinical importance
Severity 4
Treatability 3

.025% or .06% attributable increased risk estimated from combined case/control numbers

See 19955750, unpublished research (below).



Low clinical importance, Uncertain pathogenic

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

Inheritance pattern


Summary of published research, and additional commentary

Christensen et al conludes: “15% of Danish ARVC/D patients have mutations in PKP2. Our finding of previously reported disease-causing missense mutations in healthy controls raises concerns about the pathogeneity of these mutations and suggests increased susceptibility or a disease-modifying role. We recommend conservative evaluation of missense variants in ARVC/D patients, functional characterization and large-scale sequencing of healthy controls to clarify normal variation in PKP2.”

The combined case-control data from several papers reaches, at best, a p-value of 0.046. This is almost certainly biased to overrepresent the variant in cases, however, as only papers which detected S140F in their patient screens are included in this sum. Note that this p-value is actually worse than that found by Christensen et al., and those authors are cautious regarding evaluating this variant as pathogenic.

Note: This is a very rough calculation for the purposes of assigning penetrance in our evaluation, the significance for this variant is quite weak in the first place. Assuming it is real, and ARVD/C has an incidence of 1 in 10,000 in the general population (.01%), these case/control numbers suggest 0.025% attributable increased risk. Using the numbers from Christensen et al. alone implies a .06% increased attributable risk.

Total cases/controls case+ case– control+ control– p-value odds ratio
Arrhythmogenic Right Ventricular Dysplasia/Cardiomyopathy, Autos
7 328 5 845 0.0456 3.607


Allele frequency

  • A @ chr12:33031395: 0.2% (26/10758) in EVS
  • A @ chr12:32922661: 0.8% (1/128) in GET-Evidence
  • Frequency shown in summary reports: 0.2% (26/10758)


Syrris P, Ward D, Asimaki A, Sen-Chowdhry S, Ebrahim HY, Evans A, Hitomi N, Norman M, Pantazis A, Shaw AL, Elliott PM, McKenna WJ. Clinical expression of plakophilin-2 mutations in familial arrhythmogenic right ventricular cardiomyopathy. Circulation. 2006 Jan 24;113(3):356-64. Epub 2006 Jan 16. PubMed PMID: 16415378.

Seen in one out of 100 ARVC affected individuals, not seen in 400 control chromosomes (200 control individuals).

Authors describe this individual’s family as having three affected individuals with this mutation but then mention a family member meeting the “modified diagnostic criteria” that did not have it.

Cases/controls case+ case– control+ control– p-value odds ratio
Arrhythmogenic Right Ventricular Dysplasia/Cardiomyopathy, Autos
1 99 0 200 0.3333


Dalal D, Molin LH, Piccini J, Tichnell C, James C, Bomma C, Prakasa K, Towbin JA, Marcus FI, Spevak PJ, Bluemke DA, Abraham T, Russell SD, Calkins H, Judge DP. Clinical features of arrhythmogenic right ventricular dysplasia/cardiomyopathy associated with mutations in plakophilin-2. Circulation. 2006 Apr 4;113(13):1641-9. Epub 2006 Mar 20. PubMed PMID: 16549640.

Seen in one out of 58 patients with ARVD/C. Controls were only performed for novel mutations (not this variant).

Cases/controls case+ case– control+ control– p-value odds ratio
Arrhythmogenic Right Ventricular Dysplasia/Cardiomyopathy, Autos
1 57 - - - -


Behr ER, Dalageorgou C, Christiansen M, Syrris P, Hughes S, Tome Esteban MT, Rowland E, Jeffery S, McKenna WJ. Sudden arrhythmic death syndrome: familial evaluation identifies inheritable heart disease in the majority of families. Eur Heart J. 2008 Jul;29(13):1670-80. Epub 2008 May 27. PubMed PMID: 18508782.

Post-mortem ‘molecular autopsy’ of 24 SADS probands was performed, this variants was found in one family diagnosed with ARVC/D. Controls only performed for novel variants (i.e. not this variant).

Cases/controls case+ case– control+ control– p-value odds ratio
Arrhythmogenic Right Ventricular Dysplasia/Cardiomyopathy, Autos
1 23 - - - -


Christensen AH, Benn M, Tybjaerg-Hansen A, Haunso S, Svendsen JH. Missense variants in plakophilin-2 in arrhythmogenic right ventricular cardiomyopathy patients--disease-causing or innocent bystanders? Cardiology. 2010;115(2):148-54. Epub 2009 Dec 3. PubMed PMID: 19955750.

The authors found this variant among controls as well as ARVC/D, raising doubts regarding it having a pathogenic effect. Case+: 3, case-: 50, control+: 5, control-: 650.

They note that the region is not highly conserved (cattle have F at this position as well) and that two of the affected families in their study failed to show a genotype-phenotype correlation for this variant.

Cases/controls case+ case– control+ control– p-value odds ratio
Arrhythmogenic Right Ventricular Dysplasia/Cardiomyopathy, Autos
3 50 5 645 0.0173 7.740


den Haan AD, Tan BY, Zikusoka MN, Lladó LI, Jain R, Daly A, Tichnell C, James C, Amat-Alarcon N, Abraham T, Russell SD, Bluemke DA, Calkins H, Dalal D, Judge DP. Comprehensive desmosome mutation analysis in north americans with arrhythmogenic right ventricular dysplasia/cardiomyopathy. Circ Cardiovasc Genet. 2009 Oct;2(5):428-35. Epub 2009 Jun 3. PubMed PMID: 20031617; PubMed Central PMCID: PMC2801867.

Seen in one out of one hundred patients (82 unrelated ARVD/C probands and 18 unrelated individuals with suspected ARVD/C). The authors note that although it is only a single amino acid change, “it has repeatedly been found in association with ARVD/C and was not seen in over 500 control chromosomes”. The controls they perform for this study were only done for novel variants (i.e. not including this previously reported variant).

Cases/controls case+ case– control+ control– p-value odds ratio
Arrhythmogenic Right Ventricular Dysplasia/Cardiomyopathy, Autos
1 99 - - - -



hu0D879F - CGI sample GS00253-DNA_G01_200_37
het A @ chr12:33031395


Other external references

  • GeneTests records for the PKP2 gene
    Arrhythmogenic Right Ventricular Dysplasia/Cardiomyopathy, Autos
    Arrhythmogenic Right Ventricular Dysplasia/Cardiomyopathy 9
    Web search results (14 hits -- see all)
  • Missense Variants in <i>Plakophilin-2</i> in Arrhythmogenic ...
    Karger is a medical publisher, scientific publisher and biomedical publisher of print and online journals and books.
  • ESC Congress 2007 – Slides - Genotype-phenotype correlations ...
    PKP2. PKP2. ARVC/D. Dominant ARVC. Recessive ARVC. DSG2. DSG2. DSP. DSP. DSC2 ... DSP (R70X) + PKP2 (R735Q) PKP2 (C419T,S140F) + PKP2 (2146-1G>C) DSC2 (E896fsX900) DSP ...
  • Clinical Features of Arrhythmogenic Right Ventricular ...
    ... patients: those with a PKP2 mutation and those with no detectable PKP2 mutation. ... Patients with a PKP2 mutation experience ICD interventions irrespective of the ...
  • Clinical Expression of Plakophilin-2 Mutations in Familial ...
    A large number of PKP2 mutations were found in a cohort of 120 affected ... One hundred affected individuals with ARVC were examined for mutations in PKP2. ...
  • Morphologic Variants of Familial Arrhythmogenic Right ...
    Each of the enlisted PKP2 mutations detected in our study population has been ... DSG2 mutation but had 2 distinct PKP2 mutations (2146-1G>C and S140F) ...
  • Comprehensive Desmosome Mutation Analysis in North Americans ...
    Just as the rate of PKP2 mutations is different among unique cohorts, ... The mutations identified in PKP2 consisted of 2 deletions, a disruption of a ...
  • Genetics of Right Ventricular Cardiomyopathy: Genetics of ...
    Most of the reported mutations in PKP2 were identified in unrelated probands with classic ... Substitution (S140F, S615F, K654Q, C796R, respectively) Three ...
  • Type I- 97%
    ... SWISS-PROT ID Variant site Phosphorylation site SWISS-PROT variant ID ... CK1 (0.632) Con1-, abolishes the glycosylation site at position 238 8554050 NME1 ...
  • Type I- 99%
    ... belgian patient PRB2 P02812 S274P 274 VAR_019695 CK1 (0.632) Con1-, abolishes the glycosylation site at ... Polymorphism (dbSNP:rs3814211) PKP2 Q99959 S140F 140 VAR_021148 PKC ...

Other in silico analyses

  • NBLOSUM100 score = 5
  • GET-Evidence autoscore = 4

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Gene search

"GENE" or "GENE A123C":

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