Table 2.

Summary of genetic or acquired complement abnormalities identified in 21 patients with atypical hemolytic uremic syndrome who discontinued eculizumab

PtGene/AbPathogenic VariantHet/HomCommentsMAF, %PolyPhen-2 ScoreaPreviously Reported in aHUSVariant ClassificationRelapse (mo after Discontinuation)
1CFHLarge deletion in exon 1HetLarge deletion leading to quantitative FH deficiencyNovelCodon stop gainedNoPathogenic6
2CFHc.3572 C>G; p.Ser1191TrpHetVariant located in exon coding for SCR20 of FH, leading to functional deficiencyNovelProbably damaging (0.999)YesPathogenic10
3CFHc.773 C>T; p.Pro258LeuHetVariant located in exon coding for SCR; FH and C3 levels in the normal range0.00083Probably damaging (0.999)YesLikely pathogenic22
4CFHc.3048 C>A; p.Tyr1016aHomVariant located in exon coding for SCR17, leading to complete FH deficiency0.0008239Codon stop gainedNoPathogenic6
5CFHc.3572C>T; p. Ser1191LeuHetMutation located in exon coding for SCR20, leading to FH functional deficiencyNovelBenign (0.151)Yes (rs460897)Pathogenic21
6CFHc.3628C>T; p.Arg1210CysHetVariant located in exon coding for SCR20, leading to FH functional deficiency0.01730 (rs121913059)Benign (0.024)YesPathogenic
7CFHc.1789T>C; p.Cys597ArgHetVariant located in exon coding for SCR10, leading to quantitative FH deficiencyNovelProbably damaging (1)NoPathogenic3
8CFHc.3557 A>C; p.Lys1186ThrHetVariant located in exon coding for SCR20NovelPossibly damaging (0.953)NoLikely pathogenic
9CFHc.1868 G>C; p.Cys623SerHetAssociated with quantitative FH deficiencyNovelProbably damaging (1)YesPathogenic7
10CFHc.245A>G p.Lys82ArgHetVariant located in exon coding for SCR2; FH and C3 levels are in the normal range0.001649 (rs376337060)Benign (0.425)NoLikely pathogenic
11CFH-CFHR1 hybrid geneCFH-CFHR1 hybrid geneHetComplex rearrangement, leading to functional FH deficiencyNovelYesPathogenic3
12MCPc.286+1 G>CHetHeterozygous MCP deficiency (low MCP expression on granulocytes)NovelSplice regionYesPathogenic15
13MCPc.608 T>C; p.Ile203ThrHetMCP expression in the normal range; functional consequences unknownNovelNoVUS
14MCPc.286+1 G>CHetComplete MCP deficiency (low MCP expression on granulocytes)NovelSplice regionYesPathogenic
15MCPc.287–2 A>GHetHeterozygous MCP deficiency (low MCP expression on granulocytes)0.003121Splice regionYesPathogenic29
16MCPc.175C>T; p.Arg59aHetHeterozygous MCP deficiency (low MCP expression on granulocytes)NovelStop gainedYesPathogenic
17MCPc.175C>T; p.Arg59aHetHeterozygous MCP deficiency (low MCP expression on granulocytes)NovelStop gainedYesPathogenic
18MCPc.175C>T; p.Arg59aHetHeterozygous MCP deficiency (low MCP expression on granulocytes)NovelStop gainedYesPathogenic
19MCPc.350delA p.Tyr117Serfsa17HetHeterozygous MCP deficiency (low MCP expression on granulocytes)NovelStop gainedNoPathogenic5
20C3c.3100T>C; p.Trp1034ArgHetVariant located in the TED domain; no identified functional defectNovelProbably damaging (1)NoVUS
21CFIc.355G>A; p.G119RHetAssociated with quantitative FI deficiency0.05 (rs141853578)Possibly damagingYesPathogenic
22CFIc.1019 T>C; p.Ile340ThrHetVariant leading FI quantitative deficiency0.004120Probably damaging (1)YesPathogenic
23Anti-FH AbHigh titer at diagnosis (20,000 AU) with homozygous CFHR1/CFHR3 deletion; negative screening at the time of eculizumab discontinuationYes
  • Variants with documented loss or gain of function of the coded protein are classified as pathogenic variant (previously termed pathogenic mutation). Variants that are predicted to affect the function of the coded protein using bioinformatic tools (i.e., in silico PolyPhen scores or location of the variant in a domain known to be critical to the protein function) but without available functional studies or with limited documented functional effects are classified as likely pathogenic. All others variants are classified as VUS. The frequency of MAF was obtained using the ExAc database Exome Aggregation Consortium (http://exac.broadinstitute.org/about). Pt, patient; Het, heterozygous; Hom, homozygous; MAF, minor allele frequency; PolyPhen-2, Polymorphism Phenotyping v2; aHUS, atypical hemolytic uremic syndrome; CFH, complement factor H; FH, factor H; SCr, serum creatinine; MCP, membrane cofactor protein; VUS, variant of unknown significance; TED, Thioester-containing domain; CFI, complement factor I; FI, factor I.

  • a PolyPhen-2 is a tool that predicts possible effect of an amino acid substitution on the structure and function of a human protein using straightforward physical and comparative considerations (http://genetics.bwh.harvard.edu/pph2/).