CFH V62I - GET-Evidence

Curation:
Currentness:

CFH V62I

(CFH Val62Ile)


Short summary

Associated with a decreased risk for age related macular degeneration (ARMD). Homozygotes for this have a 4-5% decreased attributable risk (3-4% vs. average 8% risk), heterozygotes have slightly lower than average risk (7%). Non-carriers have an increased risk (12-13%). ARMD impairs sharp vision as age progresses. While there is no cure, treatment can slow progression of the disease and environmental factors (smoking and obesity) contribute to higher risk.

Variant evidence
Computational 1

Other variants in this gene also associated with ARMD risk

PolyPhen2: Benign, score 0.000
SIFT: Tolerated 1.00
GVGD: GV 28.68; GD 0.00; Class C0
Variant Effect Predictor (Ensembl): SIFT=tolerated(1);
PolyPhen=benign(0);
Condel=not_computable_was(-1)
Mutation Tasting Prediction: Polymorphism, P value: 0.999937; protein features (might be) affected (aa 19-82 DOMAIN Sushi 1 gets lost; aa 62-67 STRAND gets lost)

Functional -
Case/Control 5

p = 3.2 * 10^-7 (p-value is still below 1 * 10^-5 after a pessimistic estimate for multiple hypothesis correction is applied)

See Hageman GS et al. 2005 (15870199).

Familial

No familial data

 
Clinical importance
Severity 3

Vision loss in old age

Treatability 2
Penetrance 2
 

Impact

Low clinical importance, Likely protective

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

Inheritance pattern

other

Summary of published research, and additional commentary

To estimate risk of ARMD for each genotype, the following assumptions are used: (1) a lifetime risk of ARMD of 8%, (2) an average allele frequency of 55% for Val and 45% for Ile, (3) an odds ratio of 2.0 for association of Val with ARMD (when examining alleles rather than genotypes), and (4) hardy-weinberg equilibrium in the distribution of genotypes in both cases and controls.

Based on these assumptions, we’d estimate case+ (Val) allele frequency as 0.699 and the control+ (Val) allele frequency as 0.537. This satisfies the odds ratio: ( .699 / (1 – .699)) / (.537 / (1 – .537)) = 2.0 and the overall allele frequency: 0.08 * .699 + 0.92 * 0.537 = 0.55.

Using that, we can estimate the genotype frequencies for V/V, V/I, I/I in disease to be 0.48 / 0.42 / 0.09 and in controls to be 0.29 / 0.50 / 0.21. This implies the V/V genotype has a 12.6% risk (4.6% increased attributable risk vs. population average), V/I has 6.8% (1.2% decreased att. risk), and I/I has 3.6% (4.8% decreased att. risk).

Allele frequency

  • A @ chr1:196642233: 39.2% (4213/10758) in EVS
  • A @ chr1:194908855: 45.1% (55/122) in GET-Evidence
  • Frequency shown in summary reports: 39.2% (4213/10758)

Publications
 

Hageman GS, Anderson DH, Johnson LV, Hancox LS, Taiber AJ, Hardisty LI, Hageman JL, Stockman HA, Borchardt JD, Gehrs KM, Smith RJ, Silvestri G, Russell SR, Klaver CC, Barbazetto I, Chang S, Yannuzzi LA, Barile GR, Merriam JC, Smith RT, Olsh AK, Bergeron J, Zernant J, Merriam JE, Gold B, Dean M, Allikmets R. A common haplotype in the complement regulatory gene factor H (HF1/CFH) predisposes individuals to age-related macular degeneration. Proc Natl Acad Sci U S A. 2005 May 17;102(20):7227-32. Epub 2005 May 3. PubMed PMID: 15870199; PubMed Central PMCID: PMC1088171.

Table 1 reports reference variant (Val) as having significant associations with ARMD in two cohorts with odds ratios of 2.79 (p = 1.1 * 10^-4) (Iowa cohort, 228 cases & 68 controls) and 1.95 (p = 3.2 * 10^-7) (Columbia cohort, 546 cases & 261 controls). If examining from the perspective of the Ile variant these odds ratios would be inverse: 0.36 and 0.51 (protective against ARMD).

The paper notes that a total of 26 sequence variants were first detected, from which 7 were selected for the first cohort and 11 in the second. To correct for multiple hypotheses, the harshest assessment would use the highest number (26), adjusting the p-values to be 26-fold: 2.9 * 10^-3 and 8.3 * 10^-6 respectively.

Genomes
 

hu011C57 - CGI sample GS01669-DNA_B05 from PGP sample 86486261
het A @ chr1:196642233

 

hu025CEA - CGI sample GS01669-DNA_D02 from PGP sample 27316983
het A @ chr1:196642233

 

hu034DB1 - CGI sample GS00253-DNA_A02_200_37
het A @ chr1:196642233

 

hu0D879F - CGI sample GS00253-DNA_G01_200_37
het A @ chr1:196642233

 

 

hu241DEA - CGI sample GS01175-DNA_D05 from PGP sample 1205491
het A @ chr1:196642233

 

 

hu38168C - CGI sample GS01173-DNA_H06 from PGP sample 91708424
het A @ chr1:196642233

 

 

hu3CAB43 - CGI sample GS01175-DNA_D03 from PGP sample 27486199
het A @ chr1:196642233

 

hu4339C0 - CGI sample GS01175-DNA_H01 from PGP sample 94797469
het A @ chr1:196642233

 

hu604D39 - CGI sample GS00253-DNA_B02_200_37
het A @ chr1:196642233

 

 

hu8229AE - CGI sample GS01173-DNA_A07 from PGP sample 96240009
het A @ chr1:196642233

 

hu9385BA - CGI sample GS00253-DNA_E01_200_37
het A @ chr1:196642233

 

huB1FD55 - CGI sample GS01173-DNA_B07 from PGP sample 61499538
het A @ chr1:196642233

 

huCA017E - CGI sample GS01175-DNA_B01 from PGP sample 86206034
het A @ chr1:196642233

 

huFAF983 - CGI sample GS01175-DNA_F02 from PGP sample 95788191
het A @ chr1:196642233

 

GS06985 - var-GS06985-1100-36-ASM
het A @ chr1:194908856

 

GS12004 - var-GS12004-1100-36-ASM
het A @ chr1:194908856

 

GS18501 - var-GS18501-1100-36-ASM
hom A @ chr1:194908856

 

GS18502 - var-GS18502-1100-36-ASM
hom A @ chr1:194908856

 

GS18504 - var-GS18504-1100-36-ASM
hom A @ chr1:194908856

 

GS18508 - var-GS18508-1100-36-ASM
hom A @ chr1:194908856

 

GS18517 - var-GS18517-1100-36-ASM
hom A @ chr1:194908856

 

GS18537 - var-GS18537-1100-36-ASM
hom A @ chr1:194908856

 

GS18555 - var-GS18555-1100-36-ASM
hom A @ chr1:194908856

 

GS18558 - var-GS18558-1100-36-ASM
het A @ chr1:194908856

 

GS18940 - var-GS18940-1100-36-ASM
het A @ chr1:194908856

 

GS18942 - var-GS18942-1100-36-ASM
het A @ chr1:194908856

 

GS18947 - var-GS18947-1100-36-ASM
het A @ chr1:194908856

 

GS18956 - var-GS18956-1100-36-ASM
hom A @ chr1:194908856

 

GS19020 - var-GS19020-1100-36-ASM
hom A @ chr1:194908856

 

GS19026 - var-GS19026-1100-36-ASM
hom A @ chr1:194908856

 

GS19129 - var-GS19129-1100-36-ASM
hom A @ chr1:194908856

 

GS19238 - var-GS19238-1100-36-ASM
hom A @ chr1:194908856

 

GS19239 - var-GS19239-1100-36-ASM
hom A @ chr1:194908856

 

GS19240 - var-GS19240-1100-36-ASM
hom A @ chr1:194908856

 

GS19648 - var-GS19648-1100-36-ASM
het A @ chr1:194908856

 

GS19669 - var-GS19669-1100-36-ASM
het A @ chr1:194908856

 

GS19700 - var-GS19700-1100-36-ASM
het A @ chr1:194908856

 

GS19701 - var-GS19701-1100-36-ASM
het A @ chr1:194908856

 

GS19703 - var-GS19703-1100-36-ASM
hom A @ chr1:194908856

 

GS19704 - var-GS19704-1100-36-ASM
hom A @ chr1:194908856

 

GS19735 - var-GS19735-1100-36-ASM
het A @ chr1:194908856

 

GS19834 - var-GS19834-1100-36-ASM
hom A @ chr1:194908856

 

GS20509 - var-GS20509-1100-36-ASM
het A @ chr1:194908856

 

GS21767 - var-GS21767-1100-36-ASM
hom A @ chr1:194908856

 

Other external references
 

    dbSNP
  • rs800292
    www.ncbi.nlm.nih.gov/projects/SNP/snp_ref.cgi
    GeneTests
  • GeneTests records for the CFH gene
    Age-related macular degeneration
    Age-Related Macular Degeneration 4
    Atypical Hemolytic-Uremic Syndrome
    CFH-Related Atypical Hemolytic-Uremic Syndrome
    CFH-Related Dense Deposit Disease / Membranoproliferative Glomer
    Dense Deposit Disease / Membranoproliferative Glomerulonephritis
    www.ncbi.nlm.nih.gov/sites/GeneTests/lab/gene/CFH
    PolyPhen-2
  • Score: 0 (benign)
    Web search results (29 hits -- see all)
  • AceView: Gene:CFH, a comprehensive annotation of human, mouse ...
    AceView offers a comprehensive annotation of human, mouse and nematode genes reconstructed by co-alignment and clustering of all publicly available mRNAs and ESTs on ...
    ncbi.nlm.nih.gov/IEB/Research/Acembly/...&a=clones&l=CFH.1
  • Complement Factor H Variant Increases the Risk of Age-Related ...
    Table 1. CFH sequence variants identified in neovascular AMD cases ... CFH by sequencing 24 cases with severe. neovascular disease and 24 controls with no ...
    www.opt.indiana.edu/optlib/V768/Science419.pdf
  • Structure of the N-terminal Region of Complement Factor H and ...
    V62I has been suggested to be protective against AMD and ... sample of the V62I variant of FH1-2 (termed FH1-2(I62) to. distinguish it from the ...
    medicine.uiowa.edu/kidneeds/Articles/...
  • Cancer Panel Annotation
    V62I (NP_000177) 0.79. 76. rs1329423. 1. 193378044. 35. CFH. NM_001014975. intron -219. 77 ... rs2274700. 1. 193414604. 35. CFH. NM_000186. coding [82/100] SYNON ...
    snpcenter.grcf.jhmi.edu/downloads/Cancer_Panel_Annotation...
  • Structure of the N-terminal Region of Complement Factor H and ...
    ... FH has been linked to disease; V62I has been suggested to be protective against AMD and DDD (4, 25) ... regulatory gene factor H (HF1/CFH) predisposes individuals to age-related ...
    www.ncbi.nlm.nih.gov/pmc/articles/PMC2276370/?tool=pmcentrez
  • Ozark Wrap
    ... ��KO�0 ��� |L M�$MZ ��6^�xN�8 V&4ÖŽï¿½Ø ̄����MlCï ... �� �� G� -��6�� ��rĹ�ޜr�俇�Y t�ï ...
    www.ozarkhandspun.com/blog/Ozark Wrap
  • Representation of Visual Gravitational Motion in the Human ...
    Table 1. CFH sequence variants identified in neovascular AMD cases and normal controls. ... V62I. 0. 6. Exon 6. 193,380,486 A/G. R232R. 0. 2. Exon 7. rs1061147. A307A. 10 ...
    www.physik.uni-marburg.de/static/bremmer/Literature/416.pdf
  • Sunday, 28 September 2008
    syndrome in Cfh-/-.FHdelta16-20 mice. Elena Goicoechea de Jorge, Danielle Paixao ... The two AMD-associated variants of the Factor H protein (V62I and Y402H) ...
    bvet.admin.ch/tv-kurse/kurse2008/2008_09_10_international...
  • PROGRAMA DE INCENTIVACION DE LA JUBILACION DEL PDI Y PAS DE ...
    PROGRAMA DE INCENTIVACION DE LA JUBILACION DEL PDI Y PAS DE LA UPV. ... Date: Wed, 9 May 2007 13:16:23 +0200. Organization: U.P.V.. Message-ID: ...
    www.upv.es/bin/tauler?newsgroup=UPV.sindical&article=0000819
  • begin 644 4F.PDF m)5!$1btq+c0-)>+cs ...
    ... "C`P,#`P,#`V-S8@ M,#`P,#`@;@T*,#`P,#`P,3$P,2`P,#`P,"!N#0HP, ... N#0HP M,#`P,#`R,S(T(#`P,#`P(&X-"C`P,#`P,#(Y,C0@,#`P,#`@;@T*,#`P,#`P M, ...
    www.unece.org/stats/documents/ces/2005/4.f.mme

Other in silico analyses
 

  • NBLOSUM100 score = –4
  • GET-Evidence autoscore = 3

Edit history
 

Gene search

"GENE" or "GENE A123C":

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