ClinVar Miner

Submissions for variant NM_000186.4(CFH):c.3572C>T (p.Ser1191Leu)

dbSNP: rs460897
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Total submissions: 7
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Mayo Clinic Laboratories, Mayo Clinic RCV001843942 SCV002103247 pathogenic not provided 2022-01-04 criteria provided, single submitter clinical testing PM1, PM2_supporting, PS2_moderate, PS3, PS4_moderate
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV004528119 SCV002511422 pathogenic CFH-related disorder 2022-04-08 criteria provided, single submitter clinical testing Variant summary: CFH c.3572C>T (p.Ser1191Leu) results in a non-conservative amino acid change located in the last (i.e. the C-terminal) sushi/SCR/CCP repeat domain (IPR000436) of the encoded protein sequence. Four of five in-silico tools predict a benign effect of the variant on protein function. The variant was absent in 251154 control chromosomes (gnomAD v2.1). The variant, c.3572C>T, has been reported in the literature in several individuals (see HGMD, OMIM), who were affected with atypical hemolytic uremic syndrome (aHUS); notably, in a proportion of the reported cases this variant occurred in combination with Val1197Ala (including 2 proven de novo cases), as a result of a gene conversion event (see Heinen_2006). Publications reported experimental evidence evaluating an impact on protein function, and demonstrated that the variant in isolation resulted in defects of activities characteristic for the functions of C-terminal region of the protein (Heinen_2006, Merinero_2021). Of note, the variant in combination (i.e. in cis) with Val1197Ala also was associated with a defective function (Heinen_2006). One clinical diagnostic laboratory has submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation, and classified the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic.
Fulgent Genetics, Fulgent Genetics RCV002496396 SCV002807658 pathogenic Basal laminar drusen; Factor H deficiency; Hemolytic uremic syndrome, atypical, susceptibility to, 1; Age related macular degeneration 4 2024-01-08 criteria provided, single submitter clinical testing
Genome-Nilou Lab RCV003450644 SCV004177474 pathogenic Factor H deficiency 2023-04-11 criteria provided, single submitter clinical testing
Breakthrough Genomics, Breakthrough Genomics RCV000018011 SCV005088850 pathogenic Hemolytic uremic syndrome, atypical, susceptibility to, 1 2020-10-08 criteria provided, single submitter clinical testing This variant was previously reported in heterozygous, compound heterozygous and homozygous state in patients with atypical hemolytic uremic syndrome and was shown to segregate with the disease and classified as pathogenic [PMID: 10577907, 19854549, 19454698, 28596415, 20301541]. Functional studies showed the variant resulted in impaired C3b binding and a defective capacity to control complement activation on cellular surfaces [PMID: 16470555].
OMIM RCV000018011 SCV000038290 risk factor Hemolytic uremic syndrome, atypical, susceptibility to, 1 2000-05-01 no assertion criteria provided literature only
GeneReviews RCV000018011 SCV000040512 not provided Hemolytic uremic syndrome, atypical, susceptibility to, 1 no assertion provided literature only

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