ClinVar

Description

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.