ClinVar Genomic variation as it relates to human health
NM_001710.6(CFB):c.724A>C (p.Ile242Leu)
The aggregate germline classification for this variant, typically for a monogenic or Mendelian disorder as in the ACMG/AMP guidelines, or for response to a drug. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the aggregate classification.
Stars represent the aggregate review status, or the level of review supporting the aggregate germline classification for this VCV record. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the review status. The number of submissions which contribute to this review status is shown in parentheses.
Uncertain significance(2); Likely benign(5)
No data submitted for somatic clinical impact
No data submitted for oncogenicity
Variant Details
- Identifiers
-
NM_001710.6(CFB):c.724A>C (p.Ile242Leu)
Variation ID: 356279 Accession: VCV000356279.25
- Type and length
-
single nucleotide variant, 1 bp
- Location
-
Cytogenetic: 6p21.33 6: 31947807 (GRCh38) [ NCBI UCSC ] 6: 31915584 (GRCh37) [ NCBI UCSC ]
- Timeline in ClinVar
-
First in ClinVar Help The date this variant first appeared in ClinVar with each type of classification.
Last submission Help The date of the most recent submission for each type of classification for this variant.
Last evaluated Help The most recent date that a submitter evaluated this variant for each type of classification.
Germline Dec 6, 2016 May 12, 2024 Mar 1, 2024 - HGVS
-
Nucleotide Protein Molecular
consequenceNM_001710.6:c.724A>C MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_001701.2:p.Ile242Leu missense NC_000006.12:g.31947807A>C NC_000006.11:g.31915584A>C NG_008191.1:g.6864A>C LRG_136:g.6864A>C LRG_136t1:c.724A>C LRG_136p1:p.Ile242Leu P00751:p.Ile242Leu - Protein change
- I242L
- Other names
- -
- Canonical SPDI
- NC_000006.12:31947806:A:C
-
Functional
consequence HelpThe effect of the variant on RNA or protein function, based on experimental evidence from submitters.
-
-
Global minor allele
frequency (GMAF) HelpThe global minor allele frequency calculated by the 1000 Genomes Project. The minor allele at this location is indicated in parentheses and may be different from the allele represented by this VCV record.
-
0.00100 (C)
-
Allele frequency
Help
The frequency of the allele represented by this VCV record.
1000 Genomes Project 30x 0.00078
1000 Genomes Project 0.00100
NHLBI Exome Sequencing Project (ESP) Exome Variant Server 0.00154
Trans-Omics for Precision Medicine (TOPMed) 0.00169
The Genome Aggregation Database (gnomAD) 0.00175
Genes
Gene | OMIM | ClinGen Gene Dosage Sensitivity Curation |
Variation Viewer
Help
Links to Variation Viewer, a genome browser to view variation data from NCBI databases. |
Related variants | ||
---|---|---|---|---|---|---|
HI score
Help
The haploinsufficiency score for the gene, curated by ClinGen’s Dosage Sensitivity Curation task team. |
TS score
Help
The triplosensitivity score for the gene, curated by ClinGen’s Dosage Sensitivity Curation task team. |
Within gene
Help
The number of variants in ClinVar that are contained within this gene, with a link to view the list of variants. |
All
Help
The number of variants in ClinVar for this gene, including smaller variants within the gene and larger CNVs that overlap or fully contain the gene. |
|||
CFB | - | - |
GRCh38 GRCh38 GRCh38 GRCh38 GRCh38 GRCh38 GRCh38 GRCh37 |
427 | 463 |
Conditions - Germline
Condition
Help
The condition for this variant-condition (RCV) record in ClinVar. |
Classification
Help
The aggregate germline classification for this variant-condition (RCV) record in ClinVar. The number of submissions that contribute to this aggregate classification is shown in parentheses. (# of submissions) |
Review status
Help
The aggregate review status for this variant-condition (RCV) record in ClinVar. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the review status. |
Last evaluated
Help
The most recent date that a submitter evaluated this variant for the condition. |
Variation/condition record
Help
The RCV accession number, with most recent version number, for the variant-condition record, with a link to the RCV web page. |
---|---|---|---|---|
Likely benign (1) |
criteria provided, single submitter
|
Apr 27, 2017 | RCV000287217.6 | |
Conflicting interpretations of pathogenicity (2) |
criteria provided, conflicting classifications
|
Feb 14, 2023 | RCV000405609.9 | |
Conflicting interpretations of pathogenicity (3) |
criteria provided, conflicting classifications
|
Mar 1, 2024 | RCV001460839.15 | |
Uncertain significance (1) |
no assertion criteria provided
|
Aug 28, 2018 | RCV001328121.2 | |
Likely benign (1) |
criteria provided, single submitter
|
Dec 21, 2022 | RCV002509371.2 |
Submissions - Germline
Classification
Help
The submitted germline classification for each SCV record. (Last evaluated) |
Review status
Help
Stars represent the review status, or the level of review supporting the submitted (SCV) record. This value is calculated by NCBI based on data from the submitter. Read our rules for calculating the review status. This column also includes a link to the submitter’s assertion criteria if provided, and the collection method. (Assertion criteria) |
Condition
Help
The condition for the classification, provided by the submitter for this submitted (SCV) record. This column also includes the affected status and allele origin of individuals observed with this variant. |
Submitter
Help
The submitting organization for this submitted (SCV) record. This column also includes the SCV accession and version number, the date this SCV first appeared in ClinVar, and the date that this SCV was last updated in ClinVar. |
More information
Help
This column includes more information supporting the classification, including citations, the comment on classification, and detailed evidence provided as observations of the variant by the submitter. |
|
---|---|---|---|---|---|
Likely benign
(Apr 27, 2017)
|
criteria provided, single submitter
Method: clinical testing
|
Atypical hemolytic-uremic syndrome with B factor anomaly
Affected status: unknown
Allele origin:
germline
|
Illumina Laboratory Services, Illumina
Accession: SCV000462029.3
First in ClinVar: Dec 06, 2016 Last updated: May 31, 2020 |
Comment:
This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, … (more)
This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). Publications were found based on this search. The evidence from the literature, in combination with allele frequency data from public databases where available, was sufficient to determine this variant is unlikely to cause disease. Therefore, this variant is classified as likely benign. (less)
|
|
Likely benign
(Apr 27, 2017)
|
criteria provided, single submitter
Method: clinical testing
|
Macular degeneration
Affected status: unknown
Allele origin:
germline
|
Illumina Laboratory Services, Illumina
Accession: SCV000462030.3
First in ClinVar: Dec 06, 2016 Last updated: May 31, 2020 |
Comment:
This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, … (more)
This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). No publications were found based on this search. Allele frequency data from public databases allowed determination this variant is unlikely to cause disease. Therefore, this variant is classified as likely benign. (less)
|
|
Likely benign
(Dec 21, 2022)
|
criteria provided, single submitter
Method: clinical testing
|
not specified
Affected status: unknown
Allele origin:
germline
|
Women's Health and Genetics/Laboratory Corporation of America, LabCorp
Accession: SCV002819710.1
First in ClinVar: Jan 15, 2023 Last updated: Jan 15, 2023 |
Comment:
Variant summary: CFB c.724A>C (p.Ile242Leu) results in a conservative amino acid change in the encoded protein sequence. Four of five in-silico tools predict a benign … (more)
Variant summary: CFB c.724A>C (p.Ile242Leu) results in a conservative amino acid change in the encoded protein sequence. Four of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 0.00097 in 248904 control chromosomes (gnomAD). The observed variant frequency is several-fold higher than the estimated maximal expected allele frequency for a pathogenic variant in CFB causing Genetic Atypical Hemolytic Uremic Syndrome phenotype (1.3e-08), strongly suggesting that the variant is benign. c.724A>C has been reported in the literature in individuals affected with Atypical Hemolytic Uremic Syndrome (e.g. Maga_2010, Gleeson_2016, Szarvas_2016, Merrill_2017, Vaught_2018). These reports do not provide unequivocal conclusions about association of the variant with Genetic Atypical Hemolytic Uremic Syndrome. Experimental evidence evaluating an impact on protein function could not identify any clear functional consequences of the variant (Marinozzi_2014, Aradottir_2021). Marinozzi et al (2014) concluded that the variant does not fulfill the criteria to be considered as a gain of function change, and that it may be a risk factor affecting the aHUS penetrance and severity but cannot be considered as disease-causing mutation. Five ClinVar submitters (evaluation after 2014) cite the variant with conflicting assessments: likely benign (n=2), uncertain significance (n=2) and pathogenic (n=1). Based on the evidence outlined above, the variant was classified as likely benign. (less)
|
|
Uncertain significance
(Feb 14, 2023)
|
criteria provided, single submitter
Method: clinical testing
|
Atypical hemolytic-uremic syndrome with B factor anomaly
Affected status: unknown
Allele origin:
germline
|
Mendelics
Accession: SCV002518663.2
First in ClinVar: May 28, 2022 Last updated: Feb 18, 2023 |
|
|
Uncertain significance
(May 25, 2021)
|
criteria provided, single submitter
Method: clinical testing
|
Not provided
Affected status: unknown
Allele origin:
germline
|
Mayo Clinic Laboratories, Mayo Clinic
Accession: SCV001715885.1
First in ClinVar: Jun 15, 2021 Last updated: Jun 15, 2021 |
|
|
Likely benign
(Jan 30, 2024)
|
criteria provided, single submitter
Method: clinical testing
|
not provided
Affected status: unknown
Allele origin:
germline
|
Invitae
Accession: SCV001664721.4
First in ClinVar: Jun 08, 2021 Last updated: Feb 20, 2024 |
|
|
Likely benign
(Mar 01, 2024)
|
criteria provided, single submitter
Method: clinical testing
|
not provided
Affected status: yes
Allele origin:
germline
|
CeGaT Center for Human Genetics Tuebingen
Accession: SCV004810893.2
First in ClinVar: Apr 15, 2024 Last updated: May 12, 2024 |
Comment:
CFB: BP4
Number of individuals with the variant: 1
|
|
Uncertain significance
(Aug 28, 2018)
|
no assertion criteria provided
Method: clinical testing
|
Atypical hemolytic-uremic syndrome
Affected status: yes
Allele origin:
unknown
|
Sydney Genome Diagnostics, Children's Hospital Westmead
Accession: SCV001449213.1
First in ClinVar: Mar 22, 2021 Last updated: Mar 22, 2021 |
Comment:
This patient is heterozygous for a variant of uncertain significance (VOUS), c.724A>C (p.Ile242Leu), in the CFB gene. This variant (dbSNP: rs144812066) in the heterozygous state … (more)
This patient is heterozygous for a variant of uncertain significance (VOUS), c.724A>C (p.Ile242Leu), in the CFB gene. This variant (dbSNP: rs144812066) in the heterozygous state has been previously reported in patients with atypical hemolytic uremic syndrome (aHUS) (Maga et al 2010 Hum Mutat 31:E1445-60; Orandi et al 2015 Clin Pediatr (Phila) 55:308-311) however no functional studies or evidence for pathogenicity were provided. This variant has been reported in the ExAC database (http://exac.broadinstitute.org) with an allele frequency of 0.099% (116/117380 alleles). In silico analysis (Alamut Visual 2.7.7.2) is inconclusive regarding this change; Mutation Taster predicts it to be likely pathogenic whereas Align GVGD, SIFT and PolyPhen2 predicts this variant to be benign. Heterozygous variants in CFB have been reported to confer susceptibility to atypical hemolytic uremic syndrome (aHUS) (OMIM 612924). The inheritance is typically autosomal dominant and can show incomplete penetrance (Genereviews PMID: 20301541). (less)
Number of individuals with the variant: 1
|
Germline Functional Evidence
There is no functional evidence in ClinVar for this variation. If you have generated functional data for this variation, please consider submitting that data to ClinVar. |
Citations for germline classification of this variant
HelpTitle | Author | Journal | Year | Link |
---|---|---|---|---|
Factor D Inhibition Blocks Complement Activation Induced by Mutant Factor B Associated With Atypical Hemolytic Uremic Syndrome and Membranoproliferative Glomerulonephritis. | Aradottir SS | Frontiers in immunology | 2021 | PMID: 34177949 |
Germline mutations in the alternative pathway of complement predispose to HELLP syndrome. | Vaught AJ | JCI insight | 2018 | PMID: 29563339 |
Genetic testing of complement and coagulation pathways in patients with severe hypertension and renal microangiopathy. | Larsen CP | Modern pathology : an official journal of the United States and Canadian Academy of Pathology, Inc | 2018 | PMID: 29148534 |
Eculizumab cessation in atypical hemolytic uremic syndrome. | Merrill SA | Blood | 2017 | PMID: 28461395 |
Atypical haemolytic uraemic syndrome in a patient with sickle cell disease, successfully treated with eculizumab. | Chonat S | British journal of haematology | 2016 | PMID: 27870017 |
Chromosomal rearrangement-A rare cause of complement factor I associated atypical haemolytic uraemic syndrome. | Gleeson PJ | Immunobiology | 2016 | PMID: 27268256 |
Genetic analysis and functional characterization of novel mutations in a series of patients with atypical hemolytic uremic syndrome. | Szarvas N | Molecular immunology | 2016 | PMID: 26826462 |
High-Throughput Genetic Testing for Thrombotic Microangiopathies and C3 Glomerulopathies. | Bu F | Journal of the American Society of Nephrology : JASN | 2016 | PMID: 26283675 |
Fever, Jaundice, Abdominal Pain, Skin Lesions, and Dark Urine for 2 Days. | Orandi AB | Clinical pediatrics | 2016 | PMID: 26054779 |
Complement factor B mutations in atypical hemolytic uremic syndrome-disease-relevant or benign? | Marinozzi MC | Journal of the American Society of Nephrology : JASN | 2014 | PMID: 24652797 |
Mutations in alternative pathway complement proteins in American patients with atypical hemolytic uremic syndrome. | Maga TK | Human mutation | 2010 | PMID: 20513133 |
click to load more click to collapse |
Text-mined citations for rs144812066 ...
HelpRecord last updated May 12, 2024
This date represents the last time this VCV record was updated. The update may be due to an update to one of the included submitted records (SCVs), or due to an update that ClinVar made to the variant such as adding HGVS expressions or a rs number. So this date may be different from the date of the “most recent submission” reported at the top of this page.