Complement Component H Deficiency
In a patient with complement factor H deficiency (CFHD; 609814), Servais et al. (2007) identified a heterozygous mutation in the CFH gene, resulting in an arg1210-to-cys (R1210C) substitution in the SCR20 region. The patient developed glomerulonephritis with isolated C3 deposits.
Atypical Hemolytic Uremic Syndrome 1, Susceptibility To
Manuelian et al. (2003) reported a patient with atypical hemolytic uremic syndrome (AHUS1; 235400) in whom they identified a heterozygous 3701C-T transition in the CFH gene, resulting in the R1210C substitution. In vitro functional expression studies showed that the mutant protein had decreased binding to heparin, C3b/C3d, and human endothelial cells.
Age-Related Macular Degeneration 4, Susceptibility To
Raychaudhuri et al. (2011) phased genotypes for 20 common SNPs spanning the CFH-CFHR1-CFHR3 region and a common CFHR1-CFHR3 deletion in 711 individuals with advanced age-related macular degeneration (see ARMD4; 610698) and 1,041 controls, and identified a rare high-risk haplotype ('H5') that lacked both the Y402H (134370.0008) and rs10737680-rs1410996 (134370.0016) risk alleles, but contained the R1210C substitution. Genotyping R1210C in 2,423 ARMD cases and 1,122 controls demonstrated high penetrance (present in 40 cases vs 1 control; p = 7.0 x 10(-6)) and an association with a 6-year-earlier onset of disease (p = 2.3 x 10(-6)). Because R1210C is known to cause familial renal disease, Raychaudhuri et al. (2011) assessed renal function in 17 unrelated R1210C heterozygotes with advanced ARMD but found no evidence of clinically significant renal dysfunction; in addition, comparing renal function in the R1210C heterozygotes to that of 17 ARMD patients matched for disease severity, age, and gender, but without R1210C, there was no significant difference.
Zhan et al. (2013) sequenced 2,335 ARMD cases and 789 controls in 10 candidate loci (57 genes) and then augmented their control set with ancestry-matched exome-sequenced controls. An analysis of coding variation in 2,268 ARMD cases and 2,268 ancestry-matched controls identified 2 large-effect rare variants: R1210C in the CFH gene, with a case frequency of 0.51%, control frequency of 0.02%, and odds ratio of 23.11; and K155Q in the C3 gene (120700.0010), with a case frequency of 1.06%, control frequency of 0.39%, and odds ratio of 2.68. The variants suggested decreased inhibition of C3 by CFH, resulting in increased activation of the alternative complement pathway, as a key component of disease biology.
Ferrara and Seddon (2015) analyzed images from a total of 143 ARMD patients (283 eyes), including 62 patients with the R1210C variant. Patients with the R1210C variant compared to those without this variant had the highest level of macular and total macular drusen scores (57.9% vs 16.7% and 52.0% vs 14.2%, respectively; p less than .001 for both scores) as well as a greater likelihood of having advanced disease (odds ratio, 7.0; 95% CI, 3.1-16.2; p less than .001). A higher prevalence of geographic atrophy was observed among patients carrying the R1210C variant (odds ratio, 13.7%; 95% CI, 5.0-37.7; p less than .001).
