Membranoproliferative glomerulonephritis including C3 glomerulopathy

Gene: CFH

Green List (high evidence)

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.

Created: 4 Jun 2026, 11:25 a.m. | Last Modified: 4 Jun 2026, 11:25 a.m.

Panel Version: 3.9

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.

Created: 4 Jun 2026, 11:20 a.m. | Last Modified: 4 Jun 2026, 1:12 p.m.

Panel Version: 3.11

Mode of inheritance
BOTH monoallelic and biallelic, autosomal or pseudoautosomal

Phenotypes
Complement factor H deficiency, OMIM:609814; {Hemolytic uremic syndrome, atypical, susceptibility to, 1}, OMIM:235400

Publications

• 26895476
• 26283675
• 31919107
• 37615951

Green List (high evidence)

Only bi-allelic loss of function variants in CFH have been robustly linked to C3 glomerulopathy (DDD) in humans, mice and pigs. Monoalleleic defects are linked with aHUS but NOT MPGN. The mechanism for this is understood.

Created: 10 Jan 2020, 10:22 a.m. | Last Modified: 10 Jan 2020, 10:22 a.m.

Panel Version: 2.2

Mode of inheritance
BIALLELIC, autosomal or pseudoautosomal

Phenotypes
C3 glomerulopathy; Membranoproliferative glomerulonephritis; renal insufficiency; proteinuria

Publications

• PMID: 9312129

Variants in this GENE are reported as part of current diagnostic practice

I don't know

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.

Created: 22 Nov 2022, 1:51 p.m. | Last Modified: 22 Nov 2022, 1:52 p.m.

Panel Version: 2.28

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.

Created: 19 Jan 2021, 2:52 p.m. | Last Modified: 19 Jan 2021, 2:52 p.m.

Panel Version: 2.15

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

Created: 23 Mar 2020, 11:31 a.m. | Last Modified: 23 Mar 2020, 11:31 a.m.

Panel Version: 2.7

Following expert review, the mode of inheritance for this gene on this panel should be updated to BIALLELIC only.

Created: 29 Jan 2020, 10:41 p.m. | Last Modified: 29 Jan 2020, 10:41 p.m.

Panel Version: 2.2

This gene was part of an initial gene list collated by Valerie Wilson, The National Renal Complement Therapeutics Centre, February 2019 on behalf of Yorkshire and North East GLH for the GMS Renal Specialist Test Group; Gene Symbol submitted: CFH; Suggested initial gene rating: none provided;

Created: 12 Feb 2019, 12:13 p.m.

Comment when marking as ready: Marked ad ready after clinical review

Created: 15 Dec 2017, 3:31 p.m.

Green List (high evidence)

Mode of inheritance
BOTH monoallelic and biallelic, autosomal or pseudoautosomal

Phenotypes
C3 glomerulopathy; Immune complex MPGN; C3G/IC-MPGN

Publications

• 16612335
• 24722444

Green List (high evidence)

Pertinent gene . The variants known to be associated to MPGN - Genes against which can be detected with current pipeline (Single nucleotide variants/frameshifts/premature stop codon etc)

Created: 5 Jun 2017, 2:44 p.m.