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| Membranoproliferative glomerulonephritis including C3 glomerulopathy v3.14 | CFH | Ida Ertmanska changed review comment from: Comment on mode of inheritance: Meuleman et al., 2023 (PMID: 37615951) have reported more than 30 individuals with rare CFH variants and histologically confirmed C3 glomerulopathy or Ig-MPGN, with 21 patients with kidney failure at time of report. Hence, the MOI should be changed from BIALLELIC, autosomal or pseudoautosomal to BOTH monoallelic and biallelic, autosomal or pseudoautosomal for Membranoproliferative glomerulonephritis including C3 glomerulopathy.; to: Comment on mode of inheritance: Meuleman et al., 2023 (PMID: 37615951) have reported more than 30 individuals with rare monoallelic CFH variants and histologically confirmed C3 glomerulopathy or Ig-MPGN, with 21 patients with kidney failure at time of report. Hence, the MOI should be changed from BIALLELIC, autosomal or pseudoautosomal to BOTH monoallelic and biallelic, autosomal or pseudoautosomal for Membranoproliferative glomerulonephritis including C3 glomerulopathy. | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| 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). |
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| Membranoproliferative glomerulonephritis including C3 glomerulopathy v3.13 | CFI | Ida Ertmanska Phenotypes for gene: CFI were changed from C3 glomerulopathy; C3G; Immune complex MPGN; IC-MPGN; Immune-complex-mediated MPGN; Hemolytic uremic syndrome, atypical, susceptibility to, 3,612923 to {Hemolytic uremic syndrome, atypical, susceptibility to, 3}, OMIM:612923; Complement factor I deficiency, OMIM:610984; C3 glomerulopathy; C3G; Immune complex MPGN; IC-MPGN | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| 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." |
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| 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. 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. 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." |
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| Membranoproliferative glomerulonephritis including C3 glomerulopathy v3.11 | CFI | Ida Ertmanska changed review comment from: Comment on mode of inheritance: Meuleman et al., 2023 (PMID: 37615951) have reported 16 individuals with rare CFH variants and histologically confirmed C3 glomerulopathy or Ig-MPGN, with 13 patients with kidney failure at time of report. Hence, the MOI should be changed from BIALLELIC, autosomal or pseudoautosomal to BOTH monoallelic and biallelic, autosomal or pseudoautosomal for Membranoproliferative glomerulonephritis including C3 glomerulopathy.; to: Comment on mode of inheritance: Meuleman et al., 2023 (PMID: 37615951) have reported 16 individuals with rare CFI variants and histologically confirmed C3 glomerulopathy or Ig-MPGN, with 13 patients with kidney failure at time of report. Hence, the MOI should be changed from BIALLELIC, autosomal or pseudoautosomal to BOTH monoallelic and biallelic, autosomal or pseudoautosomal for Membranoproliferative glomerulonephritis including C3 glomerulopathy. | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Membranoproliferative glomerulonephritis including C3 glomerulopathy v3.11 | CFI | Ida Ertmanska commented on gene: CFI: Comment on mode of inheritance: Meuleman et al., 2023 (PMID: 37615951) have reported 16 individuals with rare CFH variants and histologically confirmed C3 glomerulopathy or Ig-MPGN, with 13 patients with kidney failure at time of report. Hence, the MOI should be changed from BIALLELIC, autosomal or pseudoautosomal to BOTH monoallelic and biallelic, autosomal or pseudoautosomal for Membranoproliferative glomerulonephritis including C3 glomerulopathy. | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| 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. |
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| 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. |
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| 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 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. 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." |
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| 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 (17 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. 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 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." |
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| 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 (13 variants, 24%), C3, and 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."; 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 (17 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. 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." |
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| Membranoproliferative glomerulonephritis including C3 glomerulopathy v3.11 | CFH | Ida Ertmanska Phenotypes for gene: CFH were changed from C3 glomerulopathy; C3G; Immune complex MPGN; IC-MPGN; Hemolytic uremic syndrome, atypical, susceptibility to, 1, 235400; Dense Deposit Disease; Membranoproliferative Glomerulonephritis Type II; Immune-complex-mediated MPGN to Complement factor H deficiency, OMIM:609814; {Hemolytic uremic syndrome, atypical, susceptibility to, 1}, OMIM:235400 | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| 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. |
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| 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 complement dysregulation driving 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. 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. |
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| 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 complement dysregulation driving disease. PMID: 34211499 Piras et al., 2021 Authors state approx 20% of cases are familial. MLPA study of patients with C3G (n = 103) and IC-MPGN (n = 96). Detected a deletion of the entire CFH, CFHR3, and CFHR1 in one patient with IC-MPGN, as well as CNVs in other CFH-related genes. 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 complement dysregulation driving 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. |
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| 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. 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 complement dysregulation driving disease. PMID: 34211499 Piras et al., 2021 Authors state approx 20% of cases are familial. MLPA study of patients with C3G (n = 103) and IC-MPGN (n = 96). Detected a deletion of the entire CFH, CFHR3, and CFHR1 in one patient with IC-MPGN, as well as CNVs in other CFH-related genes. 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. |
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| 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.; 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. 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. |
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| Membranoproliferative glomerulonephritis including C3 glomerulopathy v3.9 | CFH | Ida Ertmanska commented on gene: CFH: Comment on mode of inheritance: Meuleman et al., 2023 (PMID: 37615951) have reported more than 30 individuals with rare CFH variants and histologically confirmed C3 glomerulopathy or Ig-MPGN, with 21 patients with kidney failure at time of report. Hence, the MOI should be changed from BIALLELIC, autosomal or pseudoautosomal to BOTH monoallelic and biallelic, autosomal or pseudoautosomal for Membranoproliferative glomerulonephritis including C3 glomerulopathy. | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Membranoproliferative glomerulonephritis including C3 glomerulopathy v2.32 |
Achchuthan Shanmugasundram Panel name changed from Membranoproliferative glomerulonephritis to Membranoproliferative glomerulonephritis including C3 glomerulopathy List of related panels changed from PMG; MPGN; Primary Membranoproliferative Glomerulonephritis; Primary membranoproliferative glomerulonephritis; R197 to PMG; MPGN; Primary Membranoproliferative Glomerulonephritis; Primary membranoproliferative glomerulonephritis; Membranoproliferative glomerulonephritis; R197 |
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| Membranoproliferative glomerulonephritis including C3 glomerulopathy v2.25 | CFHR5 | Eleanor Williams Phenotypes for gene: CFHR5 were changed from C3 glomerulopathy; C3G; Immune complex MPGN; IC-MPGN; Nephropathy due to CFHR5 deficiency,614809; Immune-complex-mediated MPGN; CFHR5 nephropathy to C3 glomerulopathy; C3G; Immune complex MPGN; IC-MPGN; Nephropathy due to CFHR5 deficiency, OMIM:614809; Immune-complex-mediated MPGN; CFHR5 nephropathy; Haematuria; Chronic Kidney Disease; Proteinuria; End stage renal disease | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Membranoproliferative glomerulonephritis including C3 glomerulopathy v2.22 | CFHR5 | Daniel Gale reviewed gene: CFHR5: Rating: ; Mode of pathogenicity: Loss-of-function variants (as defined in pop up message) DO NOT cause this phenotype - please provide details in the comments; Publications: PMID: 20800271, 21566112, 30844074, 28729035, 32928961, 24067434, 27490940, 33753502, 30197990, 24067434; Phenotypes: Haematuria, C3 glomerulopathy, Chronic Kidney Disease, Proteinuria, End stage renal disease; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted; Current diagnostic: yes | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Membranoproliferative glomerulonephritis including C3 glomerulopathy v2.21 | C3 |
Ivone Leong Added comment: Comment on phenotypes: Previously: Haemolytic uraemic syndrome; aHUS; Hemolytic uremic syndrome, atypical, susceptibility to, 5,612925; C3 glomerulopathy; C3G; C3 deficiency, 613779; Immune complex MPGN; IC-MPGN |
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| Membranoproliferative glomerulonephritis including C3 glomerulopathy v2.21 | C3 | Ivone Leong Phenotypes for gene: C3 were changed from Haemolytic uraemic syndrome; aHUS; Hemolytic uremic syndrome, atypical, susceptibility to, 5,612925; C3 glomerulopathy; C3G; C3 deficiency, 613779; Immune complex MPGN; IC-MPGN to Hemolytic uremic syndrome, atypical, susceptibility to, 5, OMIM:612925; C3 glomerulopathy; C3G | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Membranoproliferative glomerulonephritis including C3 glomerulopathy v2.7 | CFH | Eleanor Williams Added comment: Comment on mode of inheritance: Updating MOI to Biallelic only, after expert reviewer notes that only biallelic variants are associated with C3 glomerulopathy. They note monoalleleic defects are linked with aHUS but NOT MPGN | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Membranoproliferative glomerulonephritis including C3 glomerulopathy v2.5 | C3 | Eleanor Williams Added comment: Comment on mode of pathogenicity: Gain of function mutations associated with familial C3G/MPGN | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Membranoproliferative glomerulonephritis including C3 glomerulopathy v2.5 | C3 | Eleanor Williams Mode of pathogenicity for gene: C3 was changed from Other to Loss-of-function variants (as defined in pop up message) DO NOT cause this phenotype - please provide details in the comments | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Membranoproliferative glomerulonephritis including C3 glomerulopathy v2.2 | C3 | Eleanor Williams commented on gene: C3: Green review by Daniel Gale agrees with Green rating and gain of function mode of pathogenicity. Should change the Mode of Pathogenicity to make it clear that Loss of function variants are not associated with the disease phenotype. | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Membranoproliferative glomerulonephritis including C3 glomerulopathy v2.2 | CFB |
Eleanor Williams changed review comment from: Associated with {Hemolytic uremic syndrome, atypical, susceptibility to, 4} (#612924) in OMIM. PMID: 28210841 - Alfakeeh et al 2017 - 7-year-old boy has pathological features compatible with IC-MPGN. A heterozygous variant p.Glu566Arg in exon 13 of the CFB gene was found. PMID: 26283675 - Bu et al 2016 - screened 193 patients using a gene panel facilitate genetic testing in aHUS, TTP, C3GN, and DDD. Report 1 variant found in a patient with aHUS and 3 in patients with C3 glomerulonephritis. Individual patient and variant information not given. PMID: 25758434 - Imamura et al 2015 - 1 family. Daughter diagnosed with C3 glomerulonephritis, mother treated for membranoproliferative glomerulonephritis, and brother with hypocomplementemia without urinary abnormalities. All 3 found to have heterozygosity for CFB p.S367R that was not present in the unaffected father or younger sister. Other variants were found in the daughter, CFI p.R201S and C3 p.V916I were excluded as in other unaffected individuals or appear in high frequency in other populations. They propose that it is highly likely that p.S367R causes a gain of function in CFB through a structure–function relationship.; to: Associated with {Hemolytic uremic syndrome, atypical, susceptibility to, 4} (#612924) in OMIM. PMID: 28210841 - Alfakeeh et al 2017 - 7-year-old boy has pathological features compatible with IC-MPGN. A heterozygous variant p.Glu566Arg in exon 13 of the CFB gene was found. Note (added 29-01-2020) - the 52 year old father was found to have the same heterozygous CFB gene variant but showed no evidence of renal function impairment, proteinuria, hematuria, or hemolysis. PMID: 26283675 - Bu et al 2016 - screened 193 patients using a gene panel facilitate genetic testing in aHUS, TTP, C3GN, and DDD. Report 1 variant found in a patient with aHUS and 3 in patients with C3 glomerulonephritis. Individual patient and variant information not given. PMID: 25758434 - Imamura et al 2015 - 1 family. Daughter diagnosed with C3 glomerulonephritis, mother treated for membranoproliferative glomerulonephritis, and brother with hypocomplementemia without urinary abnormalities. All 3 found to have heterozygosity for CFB p.S367R that was not present in the unaffected father or younger sister. Other variants were found in the daughter, CFI p.R201S and C3 p.V916I were excluded as in other unaffected individuals or appear in high frequency in other populations. They propose that it is highly likely that p.S367R causes a gain of function in CFB through a structure–function relationship. |
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| Membranoproliferative glomerulonephritis including C3 glomerulopathy v2.2 | CFI |
Eleanor Williams edited their review of gene: CFI: Added comment: Only renal phenotype in OMIM this gene is associated with is {Hemolytic uremic syndrome, atypical, susceptibility to, 3} 612923. Papers cited by the BRIDGE consortium PMID: 18371543 - Boyer et al 2008 - Patient 1 with atypical hemolytic and uremic syndrome had combined CFH and CFI heterozygous mutations. PMID: 22456601 - Servais et al 2012 - for 141 patients from 45 centers with a definite diagnosis of primary MPGN I, DDD, or GNC3 they performed direct sequencing of CFH, CFI, or MCP exons and of a set of 10 SNPs within the CFH and MCP genes. 6 patients had heterozygous variants in CFI, 3 of which are reported in patients with MPGN histology (Table 2). Following expert review rating this gene Red, and review of the literature this gene should be down graded to Amber or Red.; Changed rating: RED |
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| Membranoproliferative glomerulonephritis including C3 glomerulopathy v2.2 | CFH | Daniel Gale reviewed gene: CFH: Rating: GREEN; Mode of pathogenicity: None; Publications: PMID: 9312129; Phenotypes: C3 glomerulopathy, Membranoproliferative glomerulonephritis, renal insufficiency, proteinuria; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal; Current diagnostic: yes | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Membranoproliferative glomerulonephritis including C3 glomerulopathy v2.2 | CFB | Daniel Gale reviewed gene: CFB: Rating: RED; Mode of pathogenicity: Loss-of-function variants (as defined in pop up message) DO NOT cause this phenotype - please provide details in the comments; Publications: PMID: 25758434; Phenotypes: C3 glomerulopathy, Membranoproliferative glomerulonephritis, renal insufficiency, proteinuria; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Membranoproliferative glomerulonephritis including C3 glomerulopathy v2.2 | C3 | Daniel Gale reviewed gene: C3: Rating: GREEN; Mode of pathogenicity: Loss-of-function variants (as defined in pop up message) DO NOT cause this phenotype - please provide details in the comments; Publications: PMID: 20852386, 26471127; Phenotypes: C3 glomerulopathy, Membranoproliferative glomerulonephritis, renal insufficiency, proteinuria; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted; Current diagnostic: yes | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Membranoproliferative glomerulonephritis including C3 glomerulopathy v1.14 | CFB |
Eleanor Williams changed review comment from: Associated with {Hemolytic uremic syndrome, atypical, susceptibility to, 4} (#612924) in OMIM. PMID: 26283675 - Bu et al 2016 - screened 193 patients using a gene panel facilitate genetic testing in aHUS, TTP, C3GN, and DDD. Report 1 variant found in a patient with aHUS and 3 in patients with C3 glomerulonephritis. Individual patient and variant information not given. PMID: 25758434 - Imamura et al 2015 - 1 family. Daughter diagnosed with C3 glomerulonephritis, mother treated for membranoproliferative glomerulonephritis, and brother with hypocomplementemia without urinary abnormalities. All 3 found to have heterozygosity for CFB p.S367R that was not present in the unaffected father or younger sister. Other variants were found in the daughter, CFI p.R201S and C3 p.V916I were excluded as in other unaffected individuals or appear in high frequency in other populations. They propose that it is highly likely that p.S367R causes a gain of function in CFB through a structure–function relationship.; to: Associated with {Hemolytic uremic syndrome, atypical, susceptibility to, 4} (#612924) in OMIM. PMID: 28210841 - Alfakeeh et al 2017 - 7-year-old boy has pathological features compatible with IC-MPGN. A heterozygous variant p.Glu566Arg in exon 13 of the CFB gene was found. PMID: 26283675 - Bu et al 2016 - screened 193 patients using a gene panel facilitate genetic testing in aHUS, TTP, C3GN, and DDD. Report 1 variant found in a patient with aHUS and 3 in patients with C3 glomerulonephritis. Individual patient and variant information not given. PMID: 25758434 - Imamura et al 2015 - 1 family. Daughter diagnosed with C3 glomerulonephritis, mother treated for membranoproliferative glomerulonephritis, and brother with hypocomplementemia without urinary abnormalities. All 3 found to have heterozygosity for CFB p.S367R that was not present in the unaffected father or younger sister. Other variants were found in the daughter, CFI p.R201S and C3 p.V916I were excluded as in other unaffected individuals or appear in high frequency in other populations. They propose that it is highly likely that p.S367R causes a gain of function in CFB through a structure–function relationship. |
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| Membranoproliferative glomerulonephritis including C3 glomerulopathy v1.14 | CFB | Eleanor Williams Phenotypes for gene: CFB were changed from Haemolytic uraemic syndrome; aHUS; Hemolytic uremic syndrome, atypical, susceptibility to, 4, 612924; C3 glomerulopathy; C3G; Immune complex MPGN; IC-MPGN to Haemolytic uraemic syndrome; aHUS; Hemolytic uremic syndrome, atypical, susceptibility to, 4, 612924; C3 glomerulopathy; C3G; Immune complex MPGN; IC-MPGN; MPGN; Membranoproliferative glomerulonephritis | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Membranoproliferative glomerulonephritis including C3 glomerulopathy v1.10 | CFB |
Eleanor Williams commented on gene: CFB: Associated with {Hemolytic uremic syndrome, atypical, susceptibility to, 4} (#612924) in OMIM. PMID: 26283675 - Bu et al 2016 - screened 193 patients using a gene panel facilitate genetic testing in aHUS, TTP, C3GN, and DDD. Report 1 variant found in a patient with aHUS and 3 in patients with C3 glomerulonephritis. Individual patient and variant information not given. PMID: 25758434 - Imamura et al 2015 - 1 family. Daughter diagnosed with C3 glomerulonephritis, mother treated for membranoproliferative glomerulonephritis, and brother with hypocomplementemia without urinary abnormalities. All 3 found to have heterozygosity for CFB p.S367R that was not present in the unaffected father or younger sister. Other variants were found in the daughter, CFI p.R201S and C3 p.V916I were excluded as in other unaffected individuals or appear in high frequency in other populations. They propose that it is highly likely that p.S367R causes a gain of function in CFB through a structure–function relationship. |
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| Membranoproliferative glomerulonephritis including C3 glomerulopathy v1.10 | C3 | Eleanor Williams Classified gene: C3 as Green List (high evidence) | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Membranoproliferative glomerulonephritis including C3 glomerulopathy v1.10 | C3 | Eleanor Williams Added comment: Comment on list classification: 2 cases plus functional data and expert review green. | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Membranoproliferative glomerulonephritis including C3 glomerulopathy v1.10 | C3 | Eleanor Williams Gene: c3 has been classified as Green List (High Evidence). | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Membranoproliferative glomerulonephritis including C3 glomerulopathy v1.9 | C3 | Eleanor Williams Publications for gene: C3 were set to 24172683; 20852386; 18796626; 21902819 | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Membranoproliferative glomerulonephritis including C3 glomerulopathy v1.8 | C3 | Eleanor Williams Added comment: Comment on mode of pathogenicity: Gain of function | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Membranoproliferative glomerulonephritis including C3 glomerulopathy v1.8 | C3 | Eleanor Williams Mode of pathogenicity for gene: C3 was changed from to Other | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Membranoproliferative glomerulonephritis including C3 glomerulopathy v1.7 | C3 | Eleanor Williams Mode of inheritance for gene: C3 was changed from BOTH monoallelic and biallelic, autosomal or pseudoautosomal to MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Membranoproliferative glomerulonephritis including C3 glomerulopathy v1.6 | C3 |
Eleanor Williams commented on gene: C3: Associated with C3 deficiency (#613779) and {Hemolytic uremic syndrome, atypical, susceptibility to, 5} (#612925) in OMIM. PMID: 20852386 - Martínez-Barricarte et al 2010 - report a case a mother and her two identical twin sons with Dense deposit disease (DDD) caused by a heterozygous variant in the C3 gene. The mutation, c.2767_2774delACGGTG (C3923ΔDG) in exon 21, results in a mutated protein (C3923ΔDG) lacking 2 amino acids (Asp923 and Gly924) in the MG7 domain of C3. The deletion was only present in affected family members. Functional studies suggest a gain of function. PMID: 26471127 - Chauvet et al 2016 - report functional characterization of a C3 mutation identified in two brothers with C3GN (C3 glomerulopathy). Both carry the same c.2327T>C heterozygous mutation in the C3 gene, leading to p.I756T. The mutation was not found in the 1000 genomes or EVS databases. In vitro the C3 mutation exhibited decreased binding to CR1, resulting in less CR1-dependent cleavage of C3b by factor 1. |
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| Membranoproliferative glomerulonephritis including C3 glomerulopathy v1.6 | CFB | David Kavanagh reviewed gene: CFB: Rating: GREEN; Mode of pathogenicity: Other; Publications: 26283675, 25758434; Phenotypes: C3G, MPGN; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Membranoproliferative glomerulonephritis including C3 glomerulopathy v1.6 | C3 | David Kavanagh reviewed gene: C3: Rating: GREEN; Mode of pathogenicity: Other; Publications: 20852386, 26471127; Phenotypes: C3G, MPGN; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Membranoproliferative glomerulonephritis including C3 glomerulopathy v1.5 | C3 | Eleanor Williams reviewed gene: C3: Rating: AMBER; Mode of pathogenicity: ; Publications: ; Phenotypes: ; Mode of inheritance: | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Membranoproliferative glomerulonephritis including C3 glomerulopathy v1.4 | C3 | Eleanor Williams Source NHS GMS was added to C3. | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Membranoproliferative glomerulonephritis including C3 glomerulopathy | C3 | Arianna Tucci marked C3 as ready | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Membranoproliferative glomerulonephritis including C3 glomerulopathy | C3 | BRIDGE consortium reviewed C3 | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||