ClinVar Miner

Submissions for variant NM_001710.6(CFB):c.724A>C (p.Ile242Leu)

gnomAD frequency: 0.00175  dbSNP: rs144812066
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Total submissions: 9
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Illumina Laboratory Services, Illumina RCV000405609 SCV000462029 likely benign Atypical hemolytic-uremic syndrome with B factor anomaly 2017-04-27 criteria provided, single submitter clinical testing 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.
Illumina Laboratory Services, Illumina RCV000287217 SCV000462030 likely benign Macular degeneration 2017-04-27 criteria provided, single submitter clinical testing 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.
Labcorp Genetics (formerly Invitae), Labcorp RCV001460839 SCV001664721 likely benign not provided 2025-02-03 criteria provided, single submitter clinical testing
Mayo Clinic Laboratories, Mayo Clinic RCV001460839 SCV001715885 uncertain significance not provided 2021-05-25 criteria provided, single submitter clinical testing
Mendelics RCV000405609 SCV002518663 uncertain significance Atypical hemolytic-uremic syndrome with B factor anomaly 2023-02-14 criteria provided, single submitter clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV002509371 SCV002819710 likely benign not specified 2022-12-21 criteria provided, single submitter clinical testing 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.
CeGaT Center for Human Genetics Tuebingen RCV001460839 SCV004810893 likely benign not provided 2024-03-01 criteria provided, single submitter clinical testing CFB: BP4
GeneDx RCV001460839 SCV005325174 uncertain significance not provided 2024-02-13 criteria provided, single submitter clinical testing In silico analysis supports that this missense variant does not alter protein structure/function; This variant is associated with the following publications: (PMID: 30909646, 34426522, 26054779, 20513133, 24652797, 34177949, 27268256, 26826462, 28461395, 26283675, 37466676, 29327071, 27870017, 29148534, 29563339, 37744338, 29552364)
Sydney Genome Diagnostics, Children's Hospital Westmead RCV001328121 SCV001449213 uncertain significance Atypical hemolytic-uremic syndrome 2018-08-28 no assertion criteria provided clinical testing 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).

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