Submissions for variant NM_000186.4(CFH):c.3133+4C>G

gnomAD frequency: 0.00025  dbSNP: rs374729595

Total submissions: 11

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Eurofins Ntd Llc (ga)	RCV000735108	SCV000863307	uncertain significance	not provided	2018-09-06	criteria provided, single submitter	clinical testing
Illumina Laboratory Services, Illumina	RCV001097347	SCV001253621	uncertain significance	Age related macular degeneration 4	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, this variant could not be ruled out of causing disease and therefore its association with disease required further investigation. A literature search was performed for the gene, cDNA change, and amino acid change (if applicable). No publications were found based on this search. This variant was therefore classified as a variant of unknown significance for this disease.
Illumina Laboratory Services, Illumina	RCV001097348	SCV001253622	likely benign	Hemolytic uremic syndrome, atypical, susceptibility to, 1	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 likely benign is not then subjected to further curation. The score for this variant resulted in a classification of likely benign for this disease.
Illumina Laboratory Services, Illumina	RCV001101088	SCV001257659	uncertain significance	Basal laminar drusen	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, this variant could not be ruled out of causing disease and therefore its association with disease required further investigation. A literature search was performed for the gene, cDNA change, and amino acid change (if applicable). No publications were found based on this search. This variant was therefore classified as a variant of unknown significance for this disease.
Illumina Laboratory Services, Illumina	RCV001101089	SCV001257660	uncertain significance	CFH-Related Dense Deposit Disease / Membranoproliferative Glomerulonephritis Type II	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, this variant could not be ruled out of causing disease and therefore its association with disease required further investigation. A literature search was performed for the gene, cDNA change, and amino acid change (if applicable). No publications were found based on this search. This variant was therefore classified as a variant of unknown significance for this disease.
Mayo Clinic Laboratories, Mayo Clinic	RCV000735108	SCV001715383	uncertain significance	not provided	2021-03-30	criteria provided, single submitter	clinical testing
Labcorp Genetics (formerly Invitae), Labcorp	RCV000735108	SCV002171397	uncertain significance	not provided	2025-01-26	criteria provided, single submitter	clinical testing	This sequence change falls in intron 19 of the CFH gene. It does not directly change the encoded amino acid sequence of the CFH protein. It affects a nucleotide within the consensus splice site. This variant is present in population databases (rs374729595, gnomAD 0.05%). This variant has not been reported in the literature in individuals affected with CFH-related conditions. ClinVar contains an entry for this variant (Variation ID: 598661). Variants that disrupt the consensus splice site are a relatively common cause of aberrant splicing (PMID: 17576681, 9536098). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV004526766	SCV005039294	uncertain significance	not specified	2024-03-21	criteria provided, single submitter	clinical testing	Variant summary: CFH c.3133+4C>G alters a non-conserved nucleotide located close to a canonical splice site and therefore could affect mRNA splicing, leading to a significantly altered protein sequence. Several computational tools predict a significant impact on normal splicing: Two predict the variant weakens a 5' donor site. However, these predictions have yet to be confirmed by functional studies. The variant allele was found at a frequency of 0.00028 in 251412 control chromosomes. c.3133+4C>G has been reported in the literature in at least one compound heterozygous individual affected with atypical hemolytic uremic syndrome (e.g. Zuber_2019) and an individual affected with age-related macular degeneration (e.g. deBreuk_2021). These reports do not provide unequivocal conclusions about association of the variant with CFH-Related Disorders. 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: 31575699, 36246952). ClinVar contains an entry for this variant (Variation ID: 598661). Based on the evidence outlined above, the variant was classified as uncertain significance.
Fulgent Genetics, Fulgent Genetics	RCV005004396	SCV005631670	uncertain significance	Basal laminar drusen; Factor H deficiency; Hemolytic uremic syndrome, atypical, susceptibility to, 1; Age related macular degeneration 4	2024-06-05	criteria provided, single submitter	clinical testing
PreventionGenetics, part of Exact Sciences	RCV004535884	SCV004752294	likely benign	CFH-related disorder	2019-07-24	no assertion criteria provided	clinical testing	This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications).
Institute of Human Genetics, Univ. Regensburg, Univ. Regensburg	RCV004817965	SCV005069359	uncertain significance	Optic atrophy	2022-01-01	no assertion criteria provided	clinical testing