Submissions for variant NM_002113.3(CFHR1):c.431-2A>G

Total submissions: 2

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV003230972	SCV003929274	benign	not specified	2023-04-14	criteria provided, single submitter	clinical testing	Variant summary: CFHR1 c.431-2A>G is located in a canonical splice-site and is predicted to affect mRNA splicing resulting in a significantly altered protein due to either exon skipping, shortening, or inclusion of intronic material. Several computational tools predict a significant impact on normal splicing: Four predict the variant abolishes a 3 prime acceptor site. However, these predictions have yet to be confirmed by functional studies. The variant allele was found at a frequency of 0.00023 in 233102 control chromosomes in the gnomAD database, including 12 homozygotes. The observed variant frequency is slightly higher than the estimated maximal expected allele frequency for a pathogenic variant in CFHR1 causing Genetic Atypical Hemolytic Uremic Syndrome phenotype (0.00016), strongly suggesting that the variant is benign. To our knowledge, no occurrence of c.431-2A>G in individuals affected with Genetic Atypical Hemolytic Uremic Syndrome and no experimental evidence demonstrating its impact on protein function have been reported. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014. Based on the evidence outlined above, the variant was classified as benign.
CeGaT Center for Human Genetics Tuebingen	RCV003420623	SCV004125164	uncertain significance	not provided	2022-08-01	criteria provided, single submitter	clinical testing