Submissions for variant NM_000204.5(CFI):c.1642G>C (p.Glu548Gln)

gnomAD frequency: 0.00206  dbSNP: rs7437875

Total submissions: 10

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Illumina Laboratory Services, Illumina	RCV000403280	SCV000446861	benign	Atypical hemolytic-uremic syndrome with I factor anomaly	2018-01-13	criteria provided, single submitter	clinical testing	This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease.
Labcorp Genetics (formerly Invitae), Labcorp	RCV000911474	SCV001056540	likely benign	not provided	2024-01-23	criteria provided, single submitter	clinical testing
Baylor Genetics	RCV000403280	SCV001520426	uncertain significance	Atypical hemolytic-uremic syndrome with I factor anomaly	2019-12-24	criteria provided, single submitter	clinical testing	This variant was determined to be of uncertain significance according to ACMG Guidelines, 2015 [PMID:25741868].
Mayo Clinic Laboratories, Mayo Clinic	RCV000911474	SCV001714126	uncertain significance	not provided	2022-07-13	criteria provided, single submitter	clinical testing	BS3_supporting
Genetic Services Laboratory, University of Chicago	RCV001821053	SCV002066468	uncertain significance	not specified	2021-01-04	criteria provided, single submitter	clinical testing	DNA sequence analysis of the CFI gene demonstrated a sequence change, c.1642G>C, in exon 13 that results in an amino acid change, p.Glu548Gln. This sequence change has been described in the gnomAD database with a relatively high frequency of 0.52% in the African sub-population (dbSNP rs7437875). The p.Glu548Gln change has been reported in an individual with atypical hemolytic uremic syndrome (PMID: 27268256) and an individual with thrombotic thrombocytopenic pupura; however, this individual was also compound heterozygous for two variants in the ADAMTS13 gene (PMID: 30046676). Additionally, a different amino acid change at the same location (p.Glu548Gly) has been reported in association with atypical hemolytic uremic syndrome (PMID: 27268256). The p.Glu548Gln change affects a moderately conserved amino acid residue located in a domain of the CFI protein that is known to be functional. In-silico pathogenicity prediction tools (SIFT, PolyPhen2, Align GVGD, REVEL) provide contradictory results for the p.Glu548Gln substitution. Due to these contrasting evidences and the lack of functional studies, the clinical significance of the p.Glu548Gln change remains unknown at this time.
Genome Diagnostics Laboratory, The Hospital for Sick Children	RCV002294304	SCV002587609	uncertain significance	Atypical hemolytic-uremic syndrome	2022-07-08	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV001821053	SCV005203707	likely benign	not specified	2024-07-03	criteria provided, single submitter	clinical testing	Variant summary: CFI c.1642G>C (p.Glu548Gln) results in a conservative amino acid change in the encoded protein sequence. Three of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 0.00071 in 251290 control chromosomes, predominantly at a frequency of 0.005 within the African or African-American subpopulation in the gnomAD database. The observed variant frequency within African or African-American control individuals in the gnomAD database is approximately 50000 fold of the estimated maximal expected allele frequency for a pathogenic variant in CFI causing Genetic Atypical Hemolytic Uremic Syndrome phenotype (1e-07). c.1642G>C has been reported in the literature in individuals affected with Genetic Atypical Hemolytic Uremic Syndrome without evidence of causality (e.g. Gleeson_2016, Brocklebank_2023). These reports do not provide unequivocal conclusions about association of the variant with Genetic Atypical Hemolytic Uremic Syndrome. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. The following publications have been ascertained in the context of this evaluation (PMID: 27268256, 37369098). ClinVar contains an entry for this variant (Variation ID: 347147). Based on the evidence outlined above, the variant was classified as likely benign.
Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	RCV000911474	SCV001744280	uncertain significance	not provided		no assertion criteria provided	clinical testing
Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	RCV000911474	SCV001953383	uncertain significance	not provided		no assertion criteria provided	clinical testing
Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	RCV000911474	SCV001968059	uncertain significance	not provided		no assertion criteria provided	clinical testing