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

gnomAD frequency: 0.00175  dbSNP: rs144812066

Total submissions: 9

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).