CSRP3 W4R - GET-Evidence


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(CSRP3 Trp4Arg)

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Short summary

Implicated in causing dilated cardiomyopathy, but seen in also seen in some unaffected controls with no family history of heart disease. The significance of this variant is unclear; if it is involved in the disease, the increased risk seems to be very low and may require other genetic or environmental factors.

Variant evidence
Computational 1

Polyphen 2 predicts probably damaging

Functional 2

Mutations in this gene cause similar disease in mice. Loss of T-cap binding.

Case/Control 3

p = 0.016

See Knöll R et al. 2002 (12507422).

Familial -
Clinical importance
Severity 4

Dilated cardiomyopathy

Treatability 3

Frequency of this variant is high enough in the general population, and DCM is rare enough, that a high penetrance effect seems to be ruled out.

See Geier C et al. 2008 (18505755), unpublished research (below).



Low clinical importance, Likely pathogenic

(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

EVS data reports this variant as having 0.4% allele frequency (0.8% of individuals are carriers). This is very discordant with the prevalence of DCM (0.04%).

Data from Knoll et al. and Geier et al. implies that, if this variant is involved in the disease, it is found in 1-2% of cases — and so .0008% of individuals are estimated to have DCM and be a carrier (.04% * 2%). To be consistent with the allele frequency data, this would mean only around 0.002% of carriers develop the disease.

Total cases/controls case+ case– control+ control– p-value odds ratio
Dilated Cardiomyopathy
13 1165 2 851 0.0325 4.748


Allele frequency

  • G @ chr11:19213986: 0.4% (42/10758) in EVS
  • Frequency shown in summary reports: 0.4% (42/10758)


Knöll R, Hoshijima M, Hoffman HM, Person V, Lorenzen-Schmidt I, Bang ML, Hayashi T, Shiga N, Yasukawa H, Schaper W, McKenna W, Yokoyama M, Schork NJ, Omens JH, McCulloch AD, Kimura A, Gregorio CC, Poller W, Schaper J, Schultheiss HP, Chien KR. The cardiac mechanical stretch sensor machinery involves a Z disc complex that is defective in a subset of human dilated cardiomyopathy. Cell. 2002 Dec 27;111(7):943-55. PubMed PMID: 12507422.

Seen in 10 out of 526 DCM cases with European ethnic origin, and not seen in 320 age-matched European controls. The authors report this as “P < 0.01 by exact Fisher test”, but we calculate it to be p = 0.016 using a two-tailed Fisher’s Exact test.

In functional studies, the authors report that “the W4R mutation in MLP results in the complete loss of T-cap binding”.

Cases/controls case+ case– control+ control– p-value odds ratio
Dilated Cardiomyopathy
10 516 0 320 0.0164


Geier C, Gehmlich K, Ehler E, Hassfeld S, Perrot A, Hayess K, Cardim N, Wenzel K, Erdmann B, Krackhardt F, Posch MG, Osterziel KJ, Bublak A, Nägele H, Scheffold T, Dietz R, Chien KR, Spuler S, Fürst DO, Nürnberg P, Ozcelik C. Beyond the sarcomere: CSRP3 mutations cause hypertrophic cardiomyopathy. Hum Mol Genet. 2008 Sep 15;17(18):2753-65. Epub 2008 May 27. Erratum in: Hum Mol Genet. 2008 Nov 1;17(21):3436. Osterziel, Karl J [added]. PubMed PMID: 18505755.

Testing 652 DCM and 354 HCM patients, and 1066 chromosomes of control probands (= 533 individuals) this variant was seen in 3 DCM cases, 2 HCM, and 2 controls.

One of the three DCM families was found to have a different causative mutation (MYBPC3-Q1233X). The two controls were found to have a negative family history of heart failure. The authors conclude that “the W4R variant is not sufficient to cause cardiomyopathy”.

Cases/controls case+ case– control+ control– p-value odds ratio
Dilated Cardiomyopathy
3 649 2 531 1.0000 1.227



Other external references

  • GeneTests records for the CSRP3 gene
    Dilated Cardiomyopathy
    Familial Hypertrophic Cardiomyopathy
    CSRP3-Related Dilated Cardiomyopathy
    CSRP3-Related Familial Hypertrophic Cardiomyopathy
  • Score: 0.958 (probably damaging)

Other in silico analyses

  • NBLOSUM100 score = 7
  • GET-Evidence autoscore = 6

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Gene search

"GENE" or "GENE A123C":

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