ClinVar

Description

Variant summary: F11 c.1026G>T (p.Gly342Gly) 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, while four predict the variant creates a 5' donor site, 4 nucleotides upstream from the original site. At least one publication reported experimental evidence demonstrating that this variant affects mRNA splicing by creating a donor GT dinucleotide 4 nucleotides upstream from the normal splice site, which is predicted to result in a frameshift alteration with a premature stop codon at the protein level (Ventura_2000). The variant allele was found at a frequency of 4e-06 in 251462 control chromosomes (gnomAD). c.1026G>T has been reported in the literature in compound heterozygous individuals affected with Hereditary factor XI deficiency disease (Ventura_2000, Zucker_2007), including a family where the variant segregated with the disease. These data indicate that the variant is likely associated with disease. The following publications have been ascertained in the context of this evaluation (PMID: 11127865, 18024374). ClinVar contains an entry for this variant (Variation ID: 1458941). Based on the evidence outlined above, the variant was classified as pathogenic.