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Membranoproliferative glomerulonephritis

Gene: CFB

Green List (high evidence)

CFB (complement factor B)
EnsemblGeneIds (GRCh38): ENSG00000243649
EnsemblGeneIds (GRCh37): ENSG00000243649
OMIM: 138470, Gene2Phenotype
CFB is in 9 panels

6 reviews

Catherine Snow (Genomics England)

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

Daniel Gale (UCL)

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

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

David Kavanagh (Newcastle upon Tyne NHS hospitals trust)

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

Mode of pathogenicity
Other

Eleanor Williams (Genomics England Curator)

I don't know

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.

Arianna Tucci (Genomics England Curator)

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

BRIDGE consortium (NIHRBR-RD)

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

Details

Mode of Inheritance
MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Sources
  • Expert Review Green
  • NHS GMS
  • Expert list
Phenotypes
  • Haemolytic uraemic syndrome
  • aHUS
  • Hemolytic uremic syndrome, atypical, susceptibility to, 4, 612924
  • C3 glomerulopathy
  • C3G
  • Immune complex MPGN
  • IC-MPGN
  • MPGN
  • Membranoproliferative glomerulonephritis
Tags
for-review
OMIM
138470
Clinvar variants
Variants in CFB
Penetrance
Complete
Publications
Mode of Pathogenicity
Loss-of-function variants (as defined in pop up message) DO NOT cause this phenotype - please provide details in the comments
Panels with this gene

History Filter Activity

16 Oct 2020, Gel status: 3

Entity classified by Genomics England curator

Catherine Snow (Genomics England)

Gene: cfb has been classified as Green List (High Evidence).

24 Jun 2020, Gel status: 2

Added Tag

Eleanor Williams (Genomics England Curator)

Tag for-review tag was added to gene: CFB.

24 Mar 2020, Gel status: 2

Set mode of pathogenicity

Eleanor Williams (Genomics England Curator)

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

24 Mar 2020, Gel status: 2

Entity classified by Genomics England curator

Eleanor Williams (Genomics England Curator)

Gene: cfb has been classified as Amber List (Moderate Evidence).

15 Aug 2019, Gel status: 3

Entity classified by Genomics England curator

Eleanor Williams (Genomics England Curator)

Gene: cfb has been classified as Green List (High Evidence).

15 Aug 2019, Gel status: 2

Set Phenotypes

Eleanor Williams (Genomics England Curator)

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

15 Aug 2019, Gel status: 2

Set publications

Eleanor Williams (Genomics England Curator)

Publications for gene: CFB were set to 25758434; 17182750; 21902819

15 Aug 2019, Gel status: 2

Set mode of pathogenicity

Eleanor Williams (Genomics England Curator)

Mode of pathogenicity for gene: CFB was changed from to Other

15 Aug 2019, Gel status: 2

Set mode of inheritance

Eleanor Williams (Genomics England Curator)

Mode of inheritance for gene: CFB was changed from BOTH monoallelic and biallelic, autosomal or pseudoautosomal to MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown

12 Feb 2019, Gel status: 2

Added New Source

Eleanor Williams (Genomics England Curator)

Source NHS GMS was added to CFB.

15 Dec 2017, Gel status: 2

Panel promoted to version 1.0

Louise Daugherty (Genomics England Curator)

15th December 2017. Panel reviews were assessed, and panel was revised according to reviews and further curation by Arianna Tucci and Louise Daugherty

15 Dec 2017, Gel status: 2

Gene classified by Genomics England curator

Arianna Tucci (Genomics England Curator)

This gene has been classified as Amber List (Moderate Evidence).

5 Jun 2017, Gel status: 0

Created

Anonymous ()

CFB was created by Anonymous

5 Jun 2017, Gel status: 0

Added New Source

Anonymous ()

CFB was added to Primary Membranoproliferative Glomerulonephritispanel. Sources: Expert list