C3 R102G - GET-Evidence

Curation:
Currentness:

C3 R102G

(C3 Arg102Gly)


Short summary

This variant (also called C3F) is common in Europeans (10.2% allele frequency), and is associated with age-related macular degeneration. In the US, 1.5% of adults over 40 have the disease, but the incidence increases strongly with age (>15% in women over 80). Assuming an average lifetime risk of ~10%, heterozygous individuals have a ~13% risk and homozygous have ~20%.

Variant evidence
Computational 1

Gene is associated with the disease, amino acid change is predicted to be disruptive, but polyphen 2 predicts benign.

Functional 1

Differing binding to mononuclear cells.

Case/Control 5

p = 1e-5 and 5e-5

See Yates JR et al. 2007 (17634448).

Familial -
 
Clinical importance
Severity 3

Causes disability late in life

Treatability 2

Diet may affect progression of macular degeneration

Penetrance 3

Based on an estimated lifetime risk of 10%, increased attributable lifetime risk of this disease is ~3% for heterozygotes (total 13%), ~10% for homozygotes (total 20%).

See Yates JR et al. 2007 (17634448).

 

Impact

Moderate clinical importance, Likely pathogenic

(The "moderate 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

The incidence of age-related macular degeneration in 40 and older is 1.5%, but increases dramatically with age (above 15% in women over 80) ( http://www.nei.nih.gov/eyedata/pbd4.asp ). PMID: 9186125 implies lifetime risks in the range of 10-15%. Based on these we calculate the increased attributable risk assuming an average lifetime incidence of 10%. We estimate ~3% attributable increased risk for heterozygotes (~13% total), ~10% for homozygotes (~20% total).

Allele frequency

  • C @ chr19:6718387: 15.2% (1636/10758) in EVS
  • C @ chr19:6669386: 12.9% (16/124) in GET-Evidence
  • Frequency shown in summary reports: 15.2% (1636/10758)

Publications
 

Arvilommi H. Capacity of complement c3 phenotypes to bind on to mononuclear cells in man. Nature. 1974 Oct 25;251(5477):740-1. PubMed PMID: 4427677.

C3F and wild-type (C3S) are observed to differ in their capacity to bind on to mononuclear cells, indicating this variant has functional consequences.

Yates JR, Sepp T, Matharu BK, Khan JC, Thurlby DA, Shahid H, Clayton DG, Hayward C, Morgan J, Wright AF, Armbrecht AM, Dhillon B, Deary IJ, Redmond E, Bird AC, Moore AT; Genetic Factors in AMD Study Group. Complement C3 variant and the risk of age-related macular degeneration. N Engl J Med. 2007 Aug 9;357(6):553-61. Epub 2007 Jul 18. PubMed PMID: 17634448.

In a study of English and Scottish people with late-stage age-related macular degeneration, they found a significant positive association of this variant. With “a” designating this variant and “A” the reference allele, in the English cases: AA: 303, Aa: 242, aa: 45, controls: AA: 227, Aa: 109, aa: 14 — p = 5.9*10E-5 for the allele being associated. Replicating in Scottish subjects, cases: AA: 117, Aa: 100, aa: 22, controls: AA: 215, Aa: 103, aa: 14. p=5.0*10E-5 for allele being associated.

They estimate that the population attributable risk for this variant is 22%. Using combined data from both groups they find that the odds ratio for heterozygote carriers is 1.7 and for homozygotes is 2.6.

Genomes
 

hu034DB1 - CGI sample GS00253-DNA_A02_200_37
het C @ chr19:6718387

 

hu04FD18 - CGI sample GS00253-DNA_F01_200_37
het C @ chr19:6718387

 

 

 

 

 

hu43860C - CGI sample GS00253-DNA_A01_200_37
het C @ chr19:6718387

 

hu604D39 - CGI sample GS00253-DNA_B02_200_37
het C @ chr19:6718387

 

 

 

 

 

 

 

 

huBEDA0B - CGI sample GS00253-DNA_C01_200_37
het C @ chr19:6718387

 

 

GS10851 - var-GS10851-1100-36-ASM
het C @ chr19:6669387

 

GS21767 - var-GS21767-1100-36-ASM
hom C @ chr19:6669387

 

Other external references
 

    dbSNP
  • rs2230199
    www.ncbi.nlm.nih.gov/projects/SNP/snp_ref.cgi
    GeneTests
  • GeneTests records for the C3 gene
    Age-related macular degeneration
    Age-Related Macular Degeneration 9
    C3 Deficiency, Autosomal Recessive
    www.ncbi.nlm.nih.gov/sites/GeneTests/lab/gene/C3
    PolyPhen-2
  • Score: 0.044 (benign)

Other in silico analyses
 

  • NBLOSUM100 score = 6
  • GET-Evidence autoscore = 3

Edit history
 

Gene search

"GENE" or "GENE A123C":

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