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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.
Polyphen 2 predicts probably damaging
Mutations in this gene cause similar disease in mice. Loss of T-cap binding.
p = 0.016
See Knöll R et al. 2002 (12507422).
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See Geier C et al. 2008 (18505755), unpublished research (below).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.)
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.
Edited in this revision:
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”.
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”.