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Membranoproliferative glomerulonephritis including C3 glomerulopathy v3.13 CFI Ida Ertmanska edited their review of gene: CFI: Changed publications to: 26895476, 26283675, 31919107, 37615951
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).
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 v3.12 CFI Ida Ertmanska Publications for gene: CFI were set to 24172683; 18371543; 22456601; 27458560
Membranoproliferative glomerulonephritis including C3 glomerulopathy v3.11 CFI Ida Ertmanska Deleted their comment
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."
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."
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.
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.
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."
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."
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."
Membranoproliferative glomerulonephritis including C3 glomerulopathy v3.11 CFI Ida Ertmanska reviewed gene: CFI: Rating: GREEN; Mode of pathogenicity: None; Publications: 31919107, 37615951; Phenotypes: {Hemolytic uremic syndrome, atypical, susceptibility to, 3}, OMIM:612923, Complement factor I deficiency, OMIM:610984; Mode of inheritance: BOTH monoallelic and biallelic, autosomal or pseudoautosomal
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 v3.10 CFH Ida Ertmanska Publications for gene: CFH were set to 24172683; 16612335; 24722444; 27458560; 9312129
Membranoproliferative glomerulonephritis including C3 glomerulopathy v3.9 CFH Ida Ertmanska Tag Q2_26_MOI tag was added to gene: CFH.
Membranoproliferative glomerulonephritis including C3 glomerulopathy v3.9 CFH Ida Ertmanska edited their review of gene: CFH: Changed publications to: 26895476, 26283675, 31919107, 37615951
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.
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.
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.
Membranoproliferative glomerulonephritis including C3 glomerulopathy v3.9 CFH Ida Ertmanska edited their review of gene: CFH: Changed publications to: 37615951, 31919107
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.
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.
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 v3.9 CFH Ida Ertmanska reviewed gene: CFH: Rating: GREEN; Mode of pathogenicity: None; Publications: 37615951; Phenotypes: Complement factor H deficiency, OMIM:609814, {Hemolytic uremic syndrome, atypical, susceptibility to, 1}, OMIM:235400; Mode of inheritance: BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Membranoproliferative glomerulonephritis including C3 glomerulopathy v3.9 Achchuthan Shanmugasundram Panel version 3.8 has been signed off on 2026-05-06
Membranoproliferative glomerulonephritis including C3 glomerulopathy v3.7 Eleanor Williams Panel version 3.6 has been signed off on 2025-04-30
Membranoproliferative glomerulonephritis including C3 glomerulopathy v3.6 CFI Achchuthan Shanmugasundram Tag to_be_confirmed_NHSE was removed from gene: CFI.
Membranoproliferative glomerulonephritis including C3 glomerulopathy v3.6 CFI Achchuthan Shanmugasundram changed review comment from: The to_be_confirmed_NHSE tag has been added, as further NHSE review is required before demoting this gene to amber.; to: After NHS Genomic Medicine Service consideration, the rating of this gene has not been changed and remains green.

The following is the comment from GMS reviewers:
The target is included in current screening. Sequence data provides clinically informative information to the NRCTC. An audit of genotype:phenotype correlation is ongoing with in the NRCTC with a completion date in the New Year. We are requesting that this target remains within the panel to enable collation of audit data.
Membranoproliferative glomerulonephritis including C3 glomerulopathy v3.6 CFB Achchuthan Shanmugasundram changed review comment from: The to_be_confirmed_NHSE tag has been added, as further NHSE review is required before demoting this gene to amber.; to: After NHS Genomic Medicine Service consideration, the rating of this gene has not been changed and remains green.

The following is the comment from GMS reviewers:
The target is included in current screening. Sequence data provides clinically informative information to the NRCTC. An audit of genotype:phenotype correlation is ongoing with in the NRCTC with a completion date in the New Year. We are requesting that this target remains within the panel to enable collation of audit data.
Membranoproliferative glomerulonephritis including C3 glomerulopathy v3.6 CFB Achchuthan Shanmugasundram Tag to_be_confirmed_NHSE was removed from gene: CFB.
Membranoproliferative glomerulonephritis including C3 glomerulopathy v3.6 CFI Achchuthan Shanmugasundram Tag for-review was removed from gene: CFI.
Membranoproliferative glomerulonephritis including C3 glomerulopathy v3.6 CFB Achchuthan Shanmugasundram Tag for-review was removed from gene: CFB.
Membranoproliferative glomerulonephritis including C3 glomerulopathy v3.6 CFI Achchuthan Shanmugasundram commented on gene: CFI
Membranoproliferative glomerulonephritis including C3 glomerulopathy v3.6 CFB Achchuthan Shanmugasundram commented on gene: CFB
Membranoproliferative glomerulonephritis including C3 glomerulopathy v3.5 Eleanor Williams Panel version 3.4 has been signed off on 2024-10-30
Membranoproliferative glomerulonephritis including C3 glomerulopathy v3.4 Eleanor Williams Panel types changed to Rare Disease 100K; GMS Rare Disease Virtual; GMS Rare Disease; Component Of Super Panel; GMS signed-off
Membranoproliferative glomerulonephritis including C3 glomerulopathy v3.3 DGKE Achchuthan Shanmugasundram Tag for-review was removed from gene: DGKE.
Tag to_be_confirmed_NHSE was removed from gene: DGKE.
Membranoproliferative glomerulonephritis including C3 glomerulopathy v3.3 CFH Achchuthan Shanmugasundram Tag for-review was removed from gene: CFH.
Tag to_be_confirmed_NHSE was removed from gene: CFH.
Membranoproliferative glomerulonephritis including C3 glomerulopathy v3.1 Catherine Snow Panel version 3.0 has been signed off on 2023-03-22
Membranoproliferative glomerulonephritis including C3 glomerulopathy v3.0 Catherine Snow promoted panel to version 3.0
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
Membranoproliferative glomerulonephritis including C3 glomerulopathy v2.31 CFHR5 Achchuthan Shanmugasundram Tag Q2_22_MOI was removed from gene: CFHR5.
Tag Q2_22_NHS_review was removed from gene: CFHR5.
Membranoproliferative glomerulonephritis including C3 glomerulopathy v2.31 CFHR5 Achchuthan Shanmugasundram Classified gene: CFHR5 as Green List (high evidence)
Membranoproliferative glomerulonephritis including C3 glomerulopathy v2.31 CFHR5 Achchuthan Shanmugasundram Gene: cfhr5 has been classified as Green List (High Evidence).
Membranoproliferative glomerulonephritis including C3 glomerulopathy v2.30 CFHR5 Achchuthan Shanmugasundram commented on gene: CFHR5
Membranoproliferative glomerulonephritis including C3 glomerulopathy v2.29 CFHR5 Achchuthan Shanmugasundram Source NHS GMS was added to CFHR5.
Mode of inheritance for gene CFHR5 was changed from BOTH monoallelic and biallelic, autosomal or pseudoautosomal to MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Rating Changed from Green List (high evidence) to Red List (low evidence)
Membranoproliferative glomerulonephritis including C3 glomerulopathy v2.28 CFH Eleanor Williams changed review comment from: Comment on mode of inheritance: BIALLELIC, autosomal or pseudoautosomal; to: Comment on mode of inheritance: Changing the MOI to BIALLELIC, autosomal or pseudoautosomal as per the signed off version 2.13 (Oct 2020) and as agreed with NHSE.
Membranoproliferative glomerulonephritis including C3 glomerulopathy v2.28 CFH Eleanor Williams Added comment: Comment on mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Membranoproliferative glomerulonephritis including C3 glomerulopathy v2.28 CFH Eleanor Williams Mode of inheritance for gene: CFH was changed from BOTH monoallelic and biallelic, autosomal or pseudoautosomal to BIALLELIC, autosomal or pseudoautosomal
Membranoproliferative glomerulonephritis including C3 glomerulopathy v2.27 DGKE Eleanor Williams Added comment: Comment on mode of inheritance: Changing the MOI to BIALLELIC, autosomal or pseudoautosomal as per the signed off version 2.13 (Oct 2020) and as agreed with NHSE.
Membranoproliferative glomerulonephritis including C3 glomerulopathy v2.27 DGKE Eleanor Williams Mode of inheritance for gene: DGKE was changed from BOTH monoallelic and biallelic, autosomal or pseudoautosomal to BIALLELIC, autosomal or pseudoautosomal
Membranoproliferative glomerulonephritis including C3 glomerulopathy v2.26 CFHR2 Sarah Leigh Tag gene-checked tag was added to gene: CFHR2.
Membranoproliferative glomerulonephritis including C3 glomerulopathy v2.26 CFHR5 Eleanor Williams Tag Q2_22_NHS_review tag was added to gene: CFHR5.
Membranoproliferative glomerulonephritis including C3 glomerulopathy v2.26 CFHR5 Eleanor Williams Added comment: Comment on mode of inheritance: Daniel Gale confirms that the mode of inheritance should be monoallelic only.
Membranoproliferative glomerulonephritis including C3 glomerulopathy v2.26 CFHR5 Eleanor Williams Mode of inheritance for gene: CFHR5 was changed from BOTH monoallelic and biallelic, autosomal or pseudoautosomal to BOTH monoallelic and biallelic, autosomal or pseudoautosomal
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 v2.24 CFHR5 Eleanor Williams Publications for gene: CFHR5 were set to 24172683; 20800271; 24067434; 23728178; 27458560; 21566112; 32928961; 22503529
Membranoproliferative glomerulonephritis including C3 glomerulopathy v2.23 CFHR5 Eleanor Williams Added comment: Comment on mode of pathogenicity: Updating as per reviewer suggestion
Membranoproliferative glomerulonephritis including C3 glomerulopathy v2.23 CFHR5 Eleanor Williams Mode of pathogenicity for gene: CFHR5 was changed from 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 v2.22 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 v2.22 CFHR5 Eleanor Williams Added comment: Comment on mode of inheritance: Leaving the mode of inheritance as Both mono and biallelic just now, but only monoallelic cases confirmed so recommending a change to this mode of inheritance.
Membranoproliferative glomerulonephritis including C3 glomerulopathy v2.22 CFHR5 Eleanor Williams Mode of inheritance for gene: CFHR5 was changed from BOTH monoallelic and biallelic, autosomal or pseudoautosomal to BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Membranoproliferative glomerulonephritis including C3 glomerulopathy v2.21 CFHR5 Eleanor Williams Tag Q2_22_MOI tag was added to gene: CFHR5.
Membranoproliferative glomerulonephritis including C3 glomerulopathy v2.21 CFHR5 Eleanor Williams reviewed gene: CFHR5: Rating: ; Mode of pathogenicity: None; Publications: 20800271, 22503529, 23402027, 24334459, 24067434, 34566977; Phenotypes: Nephropathy due to CFHR5 deficiency, OMIM:614809; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Membranoproliferative glomerulonephritis including C3 glomerulopathy v2.21 DGKE Eleanor Williams Tag to_be_confirmed_NHSE tag was added to gene: DGKE.
Membranoproliferative glomerulonephritis including C3 glomerulopathy v2.21 CFH Eleanor Williams Tag to_be_confirmed_NHSE tag was added to gene: CFH.
Membranoproliferative glomerulonephritis including C3 glomerulopathy v2.21 CFI Eleanor Williams Tag to_be_confirmed_NHSE tag was added to gene: CFI.
Membranoproliferative glomerulonephritis including C3 glomerulopathy v2.21 CFB Eleanor Williams Tag to_be_confirmed_NHSE tag was added to gene: CFB.
Membranoproliferative glomerulonephritis including C3 glomerulopathy v2.21 CFB Eleanor Williams commented on gene: CFB: In OMIM this gene is also provisionally associated with Complement factor B deficiency based on evidence from one family with biallelic variants in CFB. However, given the phenotype/level of evidence it is not appropriate to change the mode of inheritance to Both monoallelic and biallelic on this panel.
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
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 v2.20 CFHR5 Sarah Leigh changed review comment from: PMID 22503529 reports a heterozygous 1bp insertion variant (rs565457964) in a child with Nephropathy due to CFHR5 deficiency OMIM:614809.; to: PMID 22503529 reports a heterozygous 1bp insertion variant (rs565457964) in a child with Nephropathy due to CFHR5 deficiency OMIM:614809 and persistent renal disease following a streptococcal infection. The variant was also seen in her unaffected mother and sister, which suggested that this variant is not sufficient to cause disease, but likely acts as a susceptibility factor for the development of glomerulonephritis.
Membranoproliferative glomerulonephritis including C3 glomerulopathy v2.20 CFHR5 Sarah Leigh commented on gene: CFHR5
Membranoproliferative glomerulonephritis including C3 glomerulopathy v2.20 CFHR5 Sarah Leigh Publications for gene: CFHR5 were set to 24172683; 20800271; 24067434; 23728178; 27458560; 21566112; 32928961
Membranoproliferative glomerulonephritis including C3 glomerulopathy v2.19 CFHR5 Sarah Leigh Publications for gene: CFHR5 were set to 24172683; 20800271; 24067434; 23728178; 27458560; 21566112; 32928961]
Membranoproliferative glomerulonephritis including C3 glomerulopathy v2.18 CFHR5 Sarah Leigh Publications for gene: CFHR5 were set to 24172683; 20800271; 24067434; 23728178; 27458560; 21566112
Membranoproliferative glomerulonephritis including C3 glomerulopathy v2.17 CFHR5 Sarah Leigh Publications for gene: CFHR5 were set to 24172683; 20800271; 24067434; 23728178; 27458560
Membranoproliferative glomerulonephritis including C3 glomerulopathy v2.16 DGKE Eleanor Williams Added comment: Comment on mode of inheritance: Reverting the mode of inheritance to BOTH monalllelic and biallelic to reflect the signed off version in March 2020. However, the recommendation is to change this to just BIALLELIC, following GMS review.
Membranoproliferative glomerulonephritis including C3 glomerulopathy v2.16 DGKE Eleanor Williams Mode of inheritance for gene: DGKE was changed from BIALLELIC, autosomal or pseudoautosomal to BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Membranoproliferative glomerulonephritis including C3 glomerulopathy v2.15 DGKE Eleanor Williams Tag for-review tag was added to gene: DGKE.
Membranoproliferative glomerulonephritis including C3 glomerulopathy v2.15 CFH Eleanor Williams Tag for-review tag was added to gene: CFH.
Membranoproliferative glomerulonephritis including C3 glomerulopathy v2.15 CFH Eleanor Williams Added comment: Comment on mode of inheritance: Reverting the mode of inheritance to BOTH monalllelic and biallelic to reflect the signed off version in March 2020. However, the recommendation is to change this to just BIALLELIC, following GMS review.
Membranoproliferative glomerulonephritis including C3 glomerulopathy v2.15 CFH Eleanor Williams Mode of inheritance for gene: CFH was changed from BIALLELIC, autosomal or pseudoautosomal to BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Membranoproliferative glomerulonephritis including C3 glomerulopathy v2.14 Catherine Snow Panel types changed to Rare Disease 100K; GMS Rare Disease Virtual; GMS Rare Disease; GMS signed-off
Panel version has been signed off
Membranoproliferative glomerulonephritis including C3 glomerulopathy v2.13 CFI Catherine Snow Tag for-review tag was added to gene: CFI.
Membranoproliferative glomerulonephritis including C3 glomerulopathy v2.13 CFB Catherine Snow Classified gene: CFB as Green List (high evidence)
Membranoproliferative glomerulonephritis including C3 glomerulopathy v2.13 CFB Catherine Snow Added comment: Comment on list classification: Changed rating to Amber to reflect NHS signed-off rating, will be examined at next panel review.
Membranoproliferative glomerulonephritis including C3 glomerulopathy v2.13 CFB Catherine Snow Gene: cfb has been classified as Green List (High Evidence).
Membranoproliferative glomerulonephritis including C3 glomerulopathy v2.12 CFI Catherine Snow Classified gene: CFI as Green List (high evidence)
Membranoproliferative glomerulonephritis including C3 glomerulopathy v2.12 CFI Catherine Snow Added comment: Comment on list classification: Changed rating to Green to reflect NHS signed-off rating, will be examined at next panel review.
Membranoproliferative glomerulonephritis including C3 glomerulopathy v2.12 CFI Catherine Snow Gene: cfi has been classified as Green List (High Evidence).
Membranoproliferative glomerulonephritis including C3 glomerulopathy v2.11 CFB Eleanor Williams Tag for-review tag was added to gene: CFB.
Membranoproliferative glomerulonephritis including C3 glomerulopathy v2.11 CFB Eleanor Williams changed review comment from: Comment on list classification: Downgrading from Green to Amber. Expert review highlights that some cases come from a gene panel screen with no segregation or additional functional data.; to: Comment on list classification: Downgrading from Green to Amber. Expert review highlights that some cases come from a gene panel screen with no segregation or additional functional data. This decision has been discussed with the Genomics England Clinical team
Membranoproliferative glomerulonephritis including C3 glomerulopathy v2.11 CFB Eleanor Williams Mode of pathogenicity for gene: CFB 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 v2.10 CFB Eleanor Williams Classified gene: CFB as Amber List (moderate evidence)
Membranoproliferative glomerulonephritis including C3 glomerulopathy v2.10 CFB Eleanor Williams Added comment: Comment on list classification: Downgrading from Green to Amber. Expert review highlights that some cases come from a gene panel screen with no segregation or additional functional data.
Membranoproliferative glomerulonephritis including C3 glomerulopathy v2.10 CFB Eleanor Williams Gene: cfb has been classified as Amber List (Moderate Evidence).
Membranoproliferative glomerulonephritis including C3 glomerulopathy v2.9 DGKE Eleanor Williams Added comment: Comment on mode of inheritance: Changing MOI to Biallelic only. All reported cases are homozygous.
Membranoproliferative glomerulonephritis including C3 glomerulopathy v2.9 DGKE Eleanor Williams Mode of inheritance for gene: DGKE was changed from BOTH monoallelic and biallelic, autosomal or pseudoautosomal to BIALLELIC, autosomal or pseudoautosomal
Membranoproliferative glomerulonephritis including C3 glomerulopathy v2.8 CFI Eleanor Williams Classified gene: CFI as Amber List (moderate evidence)
Membranoproliferative glomerulonephritis including C3 glomerulopathy v2.8 CFI Eleanor Williams Added comment: Comment on list classification: Changing rating from Green to Amber. Expert review has rated this gene red. No famililal cases reported, and cases that are reported looked at candidate genes only.
Membranoproliferative glomerulonephritis including C3 glomerulopathy v2.8 CFI Eleanor Williams Gene: cfi has been classified as Amber List (Moderate Evidence).
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 v2.7 CFH Eleanor Williams Mode of inheritance for gene: CFH was changed from BOTH monoallelic and biallelic, autosomal or pseudoautosomal to BIALLELIC, autosomal or pseudoautosomal
Membranoproliferative glomerulonephritis including C3 glomerulopathy v2.6 CFH Eleanor Williams Publications for gene: CFH were set to 24172683; 16612335; 24722444; 27458560
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 v2.4 Eleanor Williams Panel version has been signed off
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.
Membranoproliferative glomerulonephritis including C3 glomerulopathy v2.2 CFH Eleanor Williams commented on gene: CFH: Following expert review, the mode of inheritance for this gene on this panel should be updated to BIALLELIC only.
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
Membranoproliferative glomerulonephritis including C3 glomerulopathy v2.2 DGKE Eleanor Williams edited their review of gene: DGKE: Added comment: Recent review by Daniel Gale rates the gene green so no change in rating.

Checking mode of inheritance:
PMID: 23274426 - Ozaltin et al 2013 - 3 consanguineous families - 3 different homozygous variants in 9 individuals.
PMID: 28526779 - Azukaitis et al 2017 - review of 24 patients with aHUS/MPGN and variants in DGKE. The 9 cases with MPGN-like renal biopsies are those reported in Ozaltin et al 2013

Other papers cited by BRIDGE review are related to aHUS only (PMID: 23542698 and 21902819)

OMIM lists the mode of inheritance for Nephrotic syndrome, type 7, #615008 as AR.

Therefore, the mode of inheritance should be updated to BIALLELIC only.; Changed mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Membranoproliferative glomerulonephritis including C3 glomerulopathy v2.2 DGKE Daniel Gale reviewed gene: DGKE: Rating: GREEN; Mode of pathogenicity: None; Publications: PMID: 23274426; Phenotypes: Proteinuria, membranoproliferative glomerulonephritis; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal; Current diagnostic: yes
Membranoproliferative glomerulonephritis including C3 glomerulopathy v2.2 CFI Daniel Gale reviewed gene: CFI: Rating: RED; Mode of pathogenicity: None; Publications: ; Phenotypes: ; Mode of inheritance: Unknown
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 v2.1 Ellen McDonagh List of related panels changed from PMG; MPGN; Primary Membranoproliferative Glomerulonephritis; R197 to PMG; MPGN; Primary Membranoproliferative Glomerulonephritis; Primary membranoproliferative glomerulonephritis; R197
Membranoproliferative glomerulonephritis including C3 glomerulopathy v2.0 Ellen McDonagh promoted panel to version 2.0
Membranoproliferative glomerulonephritis including C3 glomerulopathy v1.17 Ellen McDonagh Panel types changed to Rare Disease 100K; GMS Rare Disease; GMS signed-off
Membranoproliferative glomerulonephritis including C3 glomerulopathy v1.16 Eleanor Williams List of related panels changed from PMG; MPGN; Primary Membranoproliferative Glomerulonephritis to PMG; MPGN; Primary Membranoproliferative Glomerulonephritis; R197
Membranoproliferative glomerulonephritis including C3 glomerulopathy v1.15 CFB Eleanor Williams Classified gene: CFB as Green List (high evidence)
Membranoproliferative glomerulonephritis including C3 glomerulopathy v1.15 CFB Eleanor Williams Added comment: Comment on list classification: Promoting from Amber to Green. Sufficient cases reported.
Membranoproliferative glomerulonephritis including C3 glomerulopathy v1.15 CFB Eleanor Williams Gene: cfb has been classified as Green List (High Evidence).
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.
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 v1.13 CFB Eleanor Williams Publications for gene: CFB were set to 25758434; 17182750; 21902819
Membranoproliferative glomerulonephritis including C3 glomerulopathy v1.12 CFB Eleanor Williams Added comment: Comment on mode of pathogenicity: Gain of function proposed
Membranoproliferative glomerulonephritis including C3 glomerulopathy v1.12 CFB Eleanor Williams Mode of pathogenicity for gene: CFB was changed from to Other
Membranoproliferative glomerulonephritis including C3 glomerulopathy v1.11 CFB Eleanor Williams Added comment: Comment on mode of inheritance: Familial case reported shows a monoallelic mode of inheritance
Membranoproliferative glomerulonephritis including C3 glomerulopathy v1.11 CFB Eleanor Williams Mode of inheritance for gene: CFB was changed from BOTH monoallelic and biallelic, autosomal or pseudoautosomal to MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
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.
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.
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 CFHR2 Anna de Burca reviewed gene: CFHR2: 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: ; Phenotypes: ; Mode of inheritance: None
Membranoproliferative glomerulonephritis including C3 glomerulopathy v1.5 CFHR1 Anna de Burca reviewed gene: CFHR1: 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: ; Phenotypes: ; Mode of inheritance: None
Membranoproliferative glomerulonephritis including C3 glomerulopathy v1.5 DGKE Eleanor Williams reviewed gene: DGKE: Rating: AMBER; Mode of pathogenicity: ; Publications: ; Phenotypes: ; Mode of inheritance:
Membranoproliferative glomerulonephritis including C3 glomerulopathy v1.5 CFB Eleanor Williams reviewed gene: CFB: Rating: AMBER; Mode of pathogenicity: ; Publications: ; Phenotypes: ; Mode of inheritance:
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 v1.5 CFI Eleanor Williams reviewed gene: CFI: Rating: AMBER; Mode of pathogenicity: ; Publications: ; Phenotypes: ; Mode of inheritance:
Membranoproliferative glomerulonephritis including C3 glomerulopathy v1.5 CFH Eleanor Williams reviewed gene: CFH: Rating: AMBER; Mode of pathogenicity: ; Publications: ; Phenotypes: ; Mode of inheritance:
Membranoproliferative glomerulonephritis including C3 glomerulopathy v1.4 DGKE Eleanor Williams Source NHS GMS was added to DGKE.
Rating Changed from Green List (high evidence) to Green List (high evidence)
Membranoproliferative glomerulonephritis including C3 glomerulopathy v1.4 CFB Eleanor Williams Source NHS GMS was added to CFB.
Membranoproliferative glomerulonephritis including C3 glomerulopathy v1.4 C3 Eleanor Williams Source NHS GMS was added to C3.
Membranoproliferative glomerulonephritis including C3 glomerulopathy v1.4 CFI Eleanor Williams Source NHS GMS was added to CFI.
Rating Changed from Green List (high evidence) to Green List (high evidence)
Membranoproliferative glomerulonephritis including C3 glomerulopathy v1.4 CFH Eleanor Williams Source NHS GMS was added to CFH.
Rating Changed from Green List (high evidence) to Green List (high evidence)
Membranoproliferative glomerulonephritis including C3 glomerulopathy v1.2 Ellen McDonagh Panel name changed from Primary Membranoproliferative Glomerulonephritis to Membranoproliferative glomerulonephritis
List of related panels changed from PMG; MPGN to PMG; MPGN; Primary Membranoproliferative Glomerulonephritis
Panel types changed to Rare Disease 100K; GMS Rare Disease
Membranoproliferative glomerulonephritis including C3 glomerulopathy DGKE Arianna Tucci marked DGKE as ready
Membranoproliferative glomerulonephritis including C3 glomerulopathy DGKE Arianna Tucci classified DGKE as Green List (high evidence)
Membranoproliferative glomerulonephritis including C3 glomerulopathy Louise Daugherty promoted panel to version 1.0
Membranoproliferative glomerulonephritis including C3 glomerulopathy CFB Arianna Tucci reviewed CFB
Membranoproliferative glomerulonephritis including C3 glomerulopathy CFB Arianna Tucci classified CFB as Amber List (moderate evidence)
Membranoproliferative glomerulonephritis including C3 glomerulopathy DGKE Arianna Tucci marked DGKE as ready
Membranoproliferative glomerulonephritis including C3 glomerulopathy DGKE Arianna Tucci classified DGKE as Amber List (moderate evidence)
Membranoproliferative glomerulonephritis including C3 glomerulopathy CD46 Arianna Tucci marked CD46 as ready
Membranoproliferative glomerulonephritis including C3 glomerulopathy C3 Arianna Tucci marked C3 as ready
Membranoproliferative glomerulonephritis including C3 glomerulopathy CFB Arianna Tucci edited their review of CFB
Membranoproliferative glomerulonephritis including C3 glomerulopathy CFB Arianna Tucci reviewed CFB
Membranoproliferative glomerulonephritis including C3 glomerulopathy CFI Arianna Tucci marked CFI as ready
Membranoproliferative glomerulonephritis including C3 glomerulopathy CFHR5 Arianna Tucci marked CFHR5 as ready
Membranoproliferative glomerulonephritis including C3 glomerulopathy CFHR2 Arianna Tucci marked CFHR2 as ready
Membranoproliferative glomerulonephritis including C3 glomerulopathy CFHR1 Arianna Tucci marked CFHR1 as ready
Membranoproliferative glomerulonephritis including C3 glomerulopathy CFH Arianna Tucci marked CFH as ready
Membranoproliferative glomerulonephritis including C3 glomerulopathy CFI Louise Daugherty classified CFI as green
Membranoproliferative glomerulonephritis including C3 glomerulopathy CFHR5 Louise Daugherty classified CFHR5 as green
Membranoproliferative glomerulonephritis including C3 glomerulopathy CFHR2 Louise Daugherty classified CFHR2 as green
Membranoproliferative glomerulonephritis including C3 glomerulopathy CFHR1 Louise Daugherty classified CFHR1 as green
Membranoproliferative glomerulonephritis including C3 glomerulopathy CFH Louise Daugherty classified CFH as green
Membranoproliferative glomerulonephritis including C3 glomerulopathy DGKE BRIDGE consortium reviewed DGKE
Membranoproliferative glomerulonephritis including C3 glomerulopathy CFI BRIDGE consortium reviewed CFI
Membranoproliferative glomerulonephritis including C3 glomerulopathy CFHR5 BRIDGE consortium reviewed CFHR5
Membranoproliferative glomerulonephritis including C3 glomerulopathy CFHR2 BRIDGE consortium reviewed CFHR2
Membranoproliferative glomerulonephritis including C3 glomerulopathy CFHR1 BRIDGE consortium reviewed CFHR1
Membranoproliferative glomerulonephritis including C3 glomerulopathy CFH BRIDGE consortium reviewed CFH
Membranoproliferative glomerulonephritis including C3 glomerulopathy CFB BRIDGE consortium reviewed CFB
Membranoproliferative glomerulonephritis including C3 glomerulopathy CD46 BRIDGE consortium commented on CD46
Membranoproliferative glomerulonephritis including C3 glomerulopathy CD46 BRIDGE consortium reviewed CD46
Membranoproliferative glomerulonephritis including C3 glomerulopathy C3 BRIDGE consortium reviewed C3
Membranoproliferative glomerulonephritis including C3 glomerulopathy CFHR1 Louise Daugherty reviewed CFHR1
Membranoproliferative glomerulonephritis including C3 glomerulopathy CFH Louise Daugherty reviewed CFH
Membranoproliferative glomerulonephritis including C3 glomerulopathy CFI Louise Daugherty reviewed CFI
Membranoproliferative glomerulonephritis including C3 glomerulopathy CFHR5 Louise Daugherty reviewed CFHR5
Membranoproliferative glomerulonephritis including C3 glomerulopathy CFHR2 Louise Daugherty reviewed CFHR2
Membranoproliferative glomerulonephritis including C3 glomerulopathy Ellen McDonagh approved panel