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24 Jun 2026	Membranoproliferative glomerulonephritis including C3 glomerulopathy v3.13	CD46	Ida Ertmanska reviewed gene: CD46: Rating: GREEN; Mode of pathogenicity: None; Publications: 17018561, 29566171; Phenotypes: {Hemolytic uremic syndrome, atypical, susceptibility to, 2}, OMIM:612922; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
04 Jun 2026	Membranoproliferative glomerulonephritis including C3 glomerulopathy v3.13	CFI	Ida Ertmanska changed review comment from: PMID: 37615951 Meuleman et al., 2023 Cohort of 398 French patients with C3 glomerulopathy ( n =296) or Ig-MPGN ( n =102). 53 rare variants were identified, including variants in CFI (16 patients, 13 variants, 24%), C3, and CFH. Thrombotic microangiopathy was present in 5/14 cases with CFI variants. 11 (84%) Pathogenic variants with decreased factor I production. Presence of a rare variant was associated with poor kidney survival. 5 variants yielded normal FI plasma levels, and 8 resulted in low FI plasma levels. 12/16 patients had confirmed C3 glomerulopathy and 4 had Ig-MPGN confirmed by histologic data. Kidney failure (dialysis or transplantation) was confirmed in 13/16 patients assessed. Authors found that CFI variants are associated with more severe C3G, and early, frequent recurrence after kidney transplantation. Of note, 90% of CFI variants identified in patients have been reported in gnomAD (most CFH variants are absent), suggesting that genetic susceptibility induced by CFI variants may be lower than those of CFH variants. Authors acknowledge the Levine et al., 2020 study that found no enrichment, but dispute the methodology: "In this large series, 45% of patients with Ig-MPGN had a low C4 level, suggesting that secondary forms with the activation of the classical pathway may have been included in the study." - low C4 points to secondary MPGN, rather than genetic complement dysregulation driving the disease. CFH genetic abnormalities were reported at 3.7% and 16% in the Italian and US cohorts (PMID: 26895476 & PMID: 26283675). In the US cohort, C3 patient cohort was enriched for rare variants in CFH, CFI, CFHR5, and CD46 genes (P<0.05). Italian study poses that "presence of mutations alone does not significantly increase the risk of Ig-MPGN or C3G, but it does so when combined with common susceptibility variants". PMID: 31919107 Levine et al., 2020 Analysis of WGS data of 165 primary membranoproliferative GN cases and 10k controls from the UK. Authors found that the MPGN cohort was not enriched for rare variants in complement factors compared to the control group. Hence, they pose that "rather than resulting from a primary genetic disorder of complement alternative pathway regulation, in most cases PMG is actually an autoimmune disease."; to: PMID: 37615951 Meuleman et al., 2023 Cohort of 398 French patients with C3 glomerulopathy ( n =296) or Ig-MPGN ( n =102). 53 rare variants were identified, including variants in CFI (16 patients, 13 variants, 24%), C3, and CFH. Thrombotic microangiopathy was present in 5/14 cases with CFI variants. 11 (84%) Pathogenic variants with decreased factor I production. Presence of a rare variant was associated with poor kidney survival. 5 variants yielded normal FI plasma levels, and 8 resulted in low FI plasma levels. 12/16 patients had confirmed C3 glomerulopathy and 4 had Ig-MPGN confirmed by histologic data. Kidney failure (dialysis or transplantation) was confirmed in 13/16 patients assessed. Authors found that CFI variants are associated with more severe C3G, and early, frequent recurrence after kidney transplantation. Of note, 90% of CFI variants identified in patients have been reported in gnomAD (most CFH variants are absent), suggesting that genetic susceptibility induced by CFI variants may be lower than those of CFH variants. Authors acknowledge the Levine et al., 2020 study that found no enrichment, but dispute the methodology: "In this large series, 45% of patients with Ig-MPGN had a low C4 level, suggesting that secondary forms with the activation of the classical pathway may have been included in the study." - low C4 points to secondary MPGN, rather than genetic complement dysregulation driving the disease. CFH genetic abnormalities were reported at 3.7% and 16% in the Italian and US cohorts (PMID: 26895476 & PMID: 26283675). In the US cohort, C3 patient cohort was enriched for rare variants in CFH, CFI, CFHR5, and CD46 genes (P<0.05). Italian study poses that "presence of mutations alone does not significantly increase the risk of Ig-MPGN or C3G, but it does so when combined with common susceptibility variants". PMID: 31919107 Levine et al., 2020 Analysis of WGS data of 165 primary membranoproliferative GN cases and 10k controls from the UK. Authors found that the MPGN cohort was not enriched for rare variants in complement factors compared to the control group. Hence, they pose that "rather than resulting from a primary genetic disorder of complement alternative pathway regulation, in most cases PMG is actually an autoimmune disease." The association between CFI and AD C3 glomerulonephriti has been classified as Moderate in ClinGen (June 2024); association with AD atypical hemolytic-uremic syndrome was ranked as Definitive (June 2023).
04 Jun 2026	Membranoproliferative glomerulonephritis including C3 glomerulopathy v3.11	CFI	Ida Ertmanska changed review comment from: PMID: 37615951 Meuleman et al., 2023 Cohort of 398 French patients with C3 glomerulopathy ( n =296) or Ig-MPGN ( n =102). 53 rare variants were identified, including variants in CFI (16 patients, 13 variants, 24%), C3, and CFH. Thrombotic microangiopathy was present in 5/14 cases with CFI variants. 11 (84%) Pathogenic variants with decreased factor I production. Presence of a rare variant was associated with poor kidney survival. 5 variants yielded normal FI plasma levels, and 8 resulted in low FI plasma levels. 12/16 patients had confirmed C3 glomerulopathy and 4 had Ig-MPGN confirmed by histologic data. Kidney failure (dialysis or transplantation) was confirmed in 13/16 patients assessed. Authors found that CFI variants are associated with more severe C3G, and early, frequent recurrence after kidney transplantation. Of note, 90% of CFI variants identified in patients have been reported in gnomAD (most CFH variants are absent), suggesting that genetic susceptibility induced by CFI variants may be lower than those of CFH variants. Authors acknowledge the Levine et al., 2020 study that found no enrichment, but dispute the methodology: "In this large series, 45% of patients with Ig-MPGN had a low C4 level, suggesting that secondary forms with the activation of the classical pathway may have been included in the study." - low C4 points to secondary MPGN, rather than genetic complement dysregulation driving the disease. PMID: 31919107 Levine et al., 2020 Analysis of WGS data of 165 primary membranoproliferative GN cases and 10k controls from the UK. Authors found that the MPGN cohort was not enriched for rare variants in complement factors compared to the control group. Hence, they pose that "rather than resulting from a primary genetic disorder of complement alternative pathway regulation, in most cases PMG is actually an autoimmune disease."; to: PMID: 37615951 Meuleman et al., 2023 Cohort of 398 French patients with C3 glomerulopathy ( n =296) or Ig-MPGN ( n =102). 53 rare variants were identified, including variants in CFI (16 patients, 13 variants, 24%), C3, and CFH. Thrombotic microangiopathy was present in 5/14 cases with CFI variants. 11 (84%) Pathogenic variants with decreased factor I production. Presence of a rare variant was associated with poor kidney survival. 5 variants yielded normal FI plasma levels, and 8 resulted in low FI plasma levels. 12/16 patients had confirmed C3 glomerulopathy and 4 had Ig-MPGN confirmed by histologic data. Kidney failure (dialysis or transplantation) was confirmed in 13/16 patients assessed. Authors found that CFI variants are associated with more severe C3G, and early, frequent recurrence after kidney transplantation. Of note, 90% of CFI variants identified in patients have been reported in gnomAD (most CFH variants are absent), suggesting that genetic susceptibility induced by CFI variants may be lower than those of CFH variants. Authors acknowledge the Levine et al., 2020 study that found no enrichment, but dispute the methodology: "In this large series, 45% of patients with Ig-MPGN had a low C4 level, suggesting that secondary forms with the activation of the classical pathway may have been included in the study." - low C4 points to secondary MPGN, rather than genetic complement dysregulation driving the disease. CFH genetic abnormalities were reported at 3.7% and 16% in the Italian and US cohorts (PMID: 26895476 & PMID: 26283675). In the US cohort, C3 patient cohort was enriched for rare variants in CFH, CFI, CFHR5, and CD46 genes (P<0.05). Italian study poses that "presence of mutations alone does not significantly increase the risk of Ig-MPGN or C3G, but it does so when combined with common susceptibility variants". PMID: 31919107 Levine et al., 2020 Analysis of WGS data of 165 primary membranoproliferative GN cases and 10k controls from the UK. Authors found that the MPGN cohort was not enriched for rare variants in complement factors compared to the control group. Hence, they pose that "rather than resulting from a primary genetic disorder of complement alternative pathway regulation, in most cases PMG is actually an autoimmune disease."
04 Jun 2026	Membranoproliferative glomerulonephritis including C3 glomerulopathy v3.11	CFH	Ida Ertmanska changed review comment from: PMID: 37615951 Meuleman et al., 2023 Cohort of 398 French patients with C3 glomerulopathy ( n =296) or Ig-MPGN ( n =102). 53 rare variants were identified, including variants in CFI, C3, and 30 variants in (57%) in CFH. 20/30 CFH variants were absent from gnomAD, and 24 were classified as Pathogenic according to ACMG criteria. Presence of a rare variant was associated with poor kidney survival. Plasma FH levels were low in 20 families, and normal in 10. 6/38 individuals were homozygous, 32 were heterozygous for CFH variants. Based on histology data, C3 glomerulopathy was confirmed in 32 patients, and Ig-MPGN in 6 individuals with CFH variants. Kidney failure (leading to dialysis or transplant) occured in 21/38 patients at time of report. Authors found that CFH variants are associated with more severe C3G, and early, frequent recurrence after kidney transplantation. Authors acknowledge the Levine et al., 2020 study that found no enrichment, but dispute the methodology: "In this large series, 45% of patients with Ig-MPGN had a low C4 level, suggesting that secondary forms with the activation of the classical pathway may have been included in the study." - low C4 points to secondary MPGN, rather than genetic complement dysregulation driving the disease. CFH genetic abnormalities were reported at 3.7% and 16% in the Italian and US cohorts (PMID: 26895476 & PMID: 26283675). In the US cohort, C3 patient cohort was enriched for rare variants in CFH, CFI, CFHR5, and CD46 genes (P<0.05). Italian study poses that "presence of mutations alone does not significantly increase the risk of Ig-MPGN or C3G, but it does so when combined with common susceptibility variants" e.g. CFH V62. PMID: 31919107 Levine et al., 2020 Analysis of WGS data of 165 primary membranoproliferative GN cases and 10k controls from the UK. Authors found that the MPGN cohort was not enriched for rare variants in complement factors compared to the control group. Hence, they pose that "rather than resulting from a primary genetic disorder of complement alternative pathway regulation, in most cases PMG is actually an autoimmune disease." The association between CFH and AR C3 glomerulonephritis has been classified as Definitive in ClinGen (Feb 2024). The gene is also associated with Semi Dominant atypical hemolytic-uremic syndrome (Definitive, July 2023). ClinGen accessed 4th June 2026.; to: PMID: 37615951 Meuleman et al., 2023 Cohort of 398 French patients with C3 glomerulopathy ( n =296) or Ig-MPGN ( n =102). 53 rare variants were identified, including variants in CFI, C3, and 30 variants in (57%) in CFH. 20/30 CFH variants were absent from gnomAD, and 24 were classified as Pathogenic according to ACMG criteria. Presence of a rare variant was associated with poor kidney survival. Plasma FH levels were low in 20 families, and normal in 10. 6/38 individuals were homozygous, 32 were heterozygous for CFH variants. Based on histology data, C3 glomerulopathy was confirmed in 32 patients, and Ig-MPGN in 6 individuals with CFH variants. Kidney failure (leading to dialysis or transplant) occured in 21/38 patients at time of report. Authors acknowledge the Levine et al., 2020 study that found no enrichment, but dispute the methodology: "In this large series, 45% of patients with Ig-MPGN had a low C4 level, suggesting that secondary forms with the activation of the classical pathway may have been included in the study." - low C4 points to secondary MPGN, rather than genetic complement dysregulation driving the disease. CFH genetic abnormalities were reported at 3.7% and 16% in the Italian and US cohorts (PMID: 26895476 & PMID: 26283675). In the US cohort, C3 patient cohort was enriched for rare variants in CFH, CFI, CFHR5, and CD46 genes (P<0.05). Italian study poses that "presence of mutations alone does not significantly increase the risk of Ig-MPGN or C3G, but it does so when combined with common susceptibility variants" e.g. CFH V62. PMID: 31919107 Levine et al., 2020 Analysis of WGS data of 165 primary membranoproliferative GN cases and 10k controls from the UK. Authors found that the MPGN cohort was not enriched for rare variants in complement factors compared to the control group. Hence, they pose that "rather than resulting from a primary genetic disorder of complement alternative pathway regulation, in most cases PMG is actually an autoimmune disease." The association between CFH and AR C3 glomerulonephritis has been classified as Definitive in ClinGen (Feb 2024). The gene is also associated with Semi Dominant atypical hemolytic-uremic syndrome (Definitive, July 2023). ClinGen accessed 4th June 2026.
04 Jun 2026	Membranoproliferative glomerulonephritis including C3 glomerulopathy v3.11	CFH	Ida Ertmanska changed review comment from: PMID: 37615951 Meuleman et al., 2023 Cohort of 398 French patients with C3 glomerulopathy ( n =296) or Ig-MPGN ( n =102). 53 rare variants were identified, including variants in CFI, C3, and 30 variants in (57%) in CFH. 20/30 CFH variants were absent from gnomAD, and 24 were classified as Pathogenic according to ACMG criteria. Presence of a rare variant was associated with poor kidney survival. Plasma FH levels were low in 20 families, and normal in 10. 6/38 individuals were homozygous, 32 were heterozygous for CFH variants. Based on histology data, C3 glomerulopathy was confirmed in 32 patients, and Ig-MPGN in 6 individuals with CFH variants. Kidney failure (leading to dialysis or transplant) occured in 21/38 patients at time of report. Authors acknowledge the Levine et al., 2020 study that found no enrichment, but dispute the methodology: "In this large series, 45% of patients with Ig-MPGN had a low C4 level, suggesting that secondary forms with the activation of the classical pathway may have been included in the study." - low C4 points to secondary MPGN, rather than genetic complement dysregulation driving the disease. CFH genetic abnormalities were reported at 3.7% and 16% in the Italian and US cohorts (PMID: 26895476 & PMID: 26283675). In the US cohort, C3 patient cohort was enriched for rare variants in CFH, CFI, CFHR5, and CD46 genes (P<0.05). Italian study poses that "presence of mutations alone does not significantly increase the risk of Ig-MPGN or C3G, but it does so when combined with common susceptibility variants" e.g. CFH V62. PMID: 31919107 Levine et al., 2020 Analysis of WGS data of 165 primary membranoproliferative GN cases and 10k controls from the UK. Authors found that the MPGN cohort was not enriched for rare variants in complement factors compared to the control group. Hence, they pose that "rather than resulting from a primary genetic disorder of complement alternative pathway regulation, in most cases PMG is actually an autoimmune disease." The association between CFH and AR C3 glomerulonephritis has been classified as Definitive in ClinGen (Feb 2024). The gene is also associated with Semi Dominant atypical hemolytic-uremic syndrome (Definitive, July 2023). ClinGen accessed 4th June 2026.; to: PMID: 37615951 Meuleman et al., 2023 Cohort of 398 French patients with C3 glomerulopathy ( n =296) or Ig-MPGN ( n =102). 53 rare variants were identified, including variants in CFI, C3, and 30 variants in (57%) in CFH. 20/30 CFH variants were absent from gnomAD, and 24 were classified as Pathogenic according to ACMG criteria. Presence of a rare variant was associated with poor kidney survival. Plasma FH levels were low in 20 families, and normal in 10. 6/38 individuals were homozygous, 32 were heterozygous for CFH variants. Based on histology data, C3 glomerulopathy was confirmed in 32 patients, and Ig-MPGN in 6 individuals with CFH variants. Kidney failure (leading to dialysis or transplant) occured in 21/38 patients at time of report. Authors found that CFH variants are associated with more severe C3G, and early, frequent recurrence after kidney transplantation. Authors acknowledge the Levine et al., 2020 study that found no enrichment, but dispute the methodology: "In this large series, 45% of patients with Ig-MPGN had a low C4 level, suggesting that secondary forms with the activation of the classical pathway may have been included in the study." - low C4 points to secondary MPGN, rather than genetic complement dysregulation driving the disease. CFH genetic abnormalities were reported at 3.7% and 16% in the Italian and US cohorts (PMID: 26895476 & PMID: 26283675). In the US cohort, C3 patient cohort was enriched for rare variants in CFH, CFI, CFHR5, and CD46 genes (P<0.05). Italian study poses that "presence of mutations alone does not significantly increase the risk of Ig-MPGN or C3G, but it does so when combined with common susceptibility variants" e.g. CFH V62. PMID: 31919107 Levine et al., 2020 Analysis of WGS data of 165 primary membranoproliferative GN cases and 10k controls from the UK. Authors found that the MPGN cohort was not enriched for rare variants in complement factors compared to the control group. Hence, they pose that "rather than resulting from a primary genetic disorder of complement alternative pathway regulation, in most cases PMG is actually an autoimmune disease." The association between CFH and AR C3 glomerulonephritis has been classified as Definitive in ClinGen (Feb 2024). The gene is also associated with Semi Dominant atypical hemolytic-uremic syndrome (Definitive, July 2023). ClinGen accessed 4th June 2026.
04 Jun 2026	Membranoproliferative glomerulonephritis including C3 glomerulopathy v3.9	CFH	Ida Ertmanska changed review comment from: PMID: 37615951 Meuleman et al., 2023 Cohort of 398 French patients with C3 glomerulopathy ( n =296) or Ig-MPGN ( n =102). 53 rare variants were identified, including variants in CFI, C3, and 30 variants in (57%) in CFH. 20/30 CFH variants were absent from gnomAD, and 24 were classified as Pathogenic according to ACMG criteria. Presence of a rare variant was associated with poor kidney survival. Plasma FH levels were low in 20 families, and normal in 10. 6/38 individuals were homozygous, 32 were heterozygous for CFH variants. Based on histology data, C3 glomerulopathy was confirmed in 32 patients, and Ig-MPGN in 6 individuals with CFH variants. Kidney failure (leading to dialysis or transplant) occured in 21/38 patients at time of report. Authors acknowledge the Levine et al., 2020 study that found no enrichment, but dispute the methodology: "In this large series, 45% of patients with Ig-MPGN had a low C4 level, suggesting that secondary forms with the activation of the classical pathway may have been included in the study." - low C4 points to secondary MPGN, rather than genetic complement dysregulation driving the disease. PMID: 31919107 Levine et al., 2020 Analysis of WGS data of 165 primary membranoproliferative GN cases and 10k controls from the UK. Authors found that the MPGN cohort was not enriched for rare variants in complement factors compared to the control group. Hence, they pose that "rather than resulting from a primary genetic disorder of complement alternative pathway regulation, in most cases PMG is actually an autoimmune disease." The association between CFH and AR C3 glomerulonephritis has been classified as Definitive in ClinGen (Feb 2024). The gene is also associated with Semi Dominant atypical hemolytic-uremic syndrome (Definitive, July 2023). ClinGen accessed 4th June 2026.; to: PMID: 37615951 Meuleman et al., 2023 Cohort of 398 French patients with C3 glomerulopathy ( n =296) or Ig-MPGN ( n =102). 53 rare variants were identified, including variants in CFI, C3, and 30 variants in (57%) in CFH. 20/30 CFH variants were absent from gnomAD, and 24 were classified as Pathogenic according to ACMG criteria. Presence of a rare variant was associated with poor kidney survival. Plasma FH levels were low in 20 families, and normal in 10. 6/38 individuals were homozygous, 32 were heterozygous for CFH variants. Based on histology data, C3 glomerulopathy was confirmed in 32 patients, and Ig-MPGN in 6 individuals with CFH variants. Kidney failure (leading to dialysis or transplant) occured in 21/38 patients at time of report. Authors acknowledge the Levine et al., 2020 study that found no enrichment, but dispute the methodology: "In this large series, 45% of patients with Ig-MPGN had a low C4 level, suggesting that secondary forms with the activation of the classical pathway may have been included in the study." - low C4 points to secondary MPGN, rather than genetic complement dysregulation driving the disease. CFH genetic abnormalities were reported at 3.7% and 16% in the Italian and US cohorts (PMID: 26895476 & PMID: 26283675). In the US cohort, C3 patient cohort was enriched for rare variants in CFH, CFI, CFHR5, and CD46 genes (P<0.05). Italian study poses that "presence of mutations alone does not significantly increase the risk of Ig-MPGN or C3G, but it does so when combined with common susceptibility variants" e.g. CFH V62. PMID: 31919107 Levine et al., 2020 Analysis of WGS data of 165 primary membranoproliferative GN cases and 10k controls from the UK. Authors found that the MPGN cohort was not enriched for rare variants in complement factors compared to the control group. Hence, they pose that "rather than resulting from a primary genetic disorder of complement alternative pathway regulation, in most cases PMG is actually an autoimmune disease." The association between CFH and AR C3 glomerulonephritis has been classified as Definitive in ClinGen (Feb 2024). The gene is also associated with Semi Dominant atypical hemolytic-uremic syndrome (Definitive, July 2023). ClinGen accessed 4th June 2026.
15 Dec 2017	Membranoproliferative glomerulonephritis including C3 glomerulopathy	CD46	Arianna Tucci marked CD46 as ready
05 Jun 2017	Membranoproliferative glomerulonephritis including C3 glomerulopathy	CD46	BRIDGE consortium commented on CD46
05 Jun 2017	Membranoproliferative glomerulonephritis including C3 glomerulopathy	CD46	BRIDGE consortium reviewed CD46