Membranoproliferative glomerulonephritis including C3 glomerulopathy

Gene: CFB

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.

Created: 4 Dec 2024, 10:37 p.m. | Last Modified: 6 Dec 2024, 10:38 a.m.

Panel Version: 3.6

Comment on list classification: Changed rating to Amber to reflect NHS signed-off rating, will be examined at next panel review.

Created: 16 Oct 2020, 8:11 a.m. | Last Modified: 16 Oct 2020, 8:11 a.m.

Panel Version: 2.13

Red List (low evidence)

I am only aware of a single report in which a heterozygous rare CFB variant co-segregates with C3G, and this is only in 3 individuals in a single family with no attempt at functional characterisation of the mutation. All other reports are of single missense variants ascertained by panel sequencing in a cohort of non-familial cases of MPGN/C3G and therefore are not distinguishable from noise.
Loss of function variants would be predicted to be NON-PATHOGENIC as this is a complement activator.

Created: 10 Jan 2020, 10:18 a.m. | Last Modified: 10 Jan 2020, 10:18 a.m.

Panel Version: 2.2

Mode of inheritance
MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted

Phenotypes
C3 glomerulopathy; Membranoproliferative glomerulonephritis; renal insufficiency; proteinuria

Publications

• PMID: 25758434

Mode of pathogenicity
Loss-of-function variants (as defined in pop up message) DO NOT cause this phenotype - please provide details in the comments

Green List (high evidence)

Gain of function mutations associated with familial C3G

Created: 6 Aug 2019, 10:09 a.m. | Last Modified: 6 Aug 2019, 10:09 a.m.

Panel Version: 1.6

Mode of inheritance
MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown

Phenotypes
C3G; MPGN

Publications

• 26283675
• 25758434

Mode of pathogenicity
Other

I don't know

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.

Created: 14 Oct 2021, 11:10 a.m. | Last Modified: 14 Oct 2021, 11:10 a.m.

Panel Version: 2.21

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

Created: 24 Mar 2020, 1:24 p.m. | Last Modified: 24 Mar 2020, 1:30 p.m.

Panel Version: 2.11

Comment on list classification: Promoting from Amber to Green. Sufficient cases reported.

Created: 15 Aug 2019, 9:46 a.m. | Last Modified: 15 Aug 2019, 9:46 a.m.

Panel Version: 1.15

Comment on mode of pathogenicity: Gain of function proposed

Created: 15 Aug 2019, 9:37 a.m. | Last Modified: 15 Aug 2019, 9:37 a.m.

Panel Version: 1.12

Comment on mode of inheritance: Familial case reported shows a monoallelic mode of inheritance

Created: 15 Aug 2019, 9:37 a.m. | Last Modified: 15 Aug 2019, 9:37 a.m.

Panel Version: 1.11

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.

Created: 15 Aug 2019, 9:36 a.m. | Last Modified: 29 Jan 2020, 10:50 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: CFB; Suggested initial gene rating: none provided;

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

I don't know

I found a paper 25758434 describes the first case of familial C3 glomerulonephritis (C3GN) associated with mutations in the gene for complement factor B (CFB), in one family. This evidence may not be enough to promote the gene to green, hence marked as amber

Created: 15 Dec 2017, 4:33 p.m.

Mode of inheritance
MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted

Publications

• 25758434

Red List (low evidence)

Novel gene currently associated to atypical haemolytic uraemic syndrome (aHUS), but are thought to be also causative for MPGN. PMID: 17182750 study of patients with atypical haemolytic uraemic syndrome, not PMG. Because of the variable expressivity of some complement gene mutations, we have included the genes known to cause (and in routine clinical testing in) the mechanistically related, extremely rare disease atypical Haemolytic Uraemic Syndrome (aHUS). There is now good evidence that mutations that are associated with aHUS can be found in patients with Primary MPGN/C3G (see Servais et al PMID: 22456601). Therefore known or clearly pathogenic mutations previously associated with aHUS would be presumed to be causative in patients with PMG where this is the clinical presentation.

Created: 5 Jun 2017, 3:49 p.m.

Mode of inheritance
BOTH monoallelic and biallelic, autosomal or pseudoautosomal

Phenotypes
Haemolytic uraemic syndrome; aHUS; Hemolytic uremic syndrome, atypical, susceptibility to, 4, 612924; C3 glomerulopathy; C3G; Immune complex MPGN; IC-MPGN

Publications

• 25758434
• 17182750
• 25758434
• 21902819