Submissions for variant NM_000128.4(F11):c.1853T>G (p.Ile618Ser)

gnomAD frequency: 0.00002  dbSNP: rs281875276

Total submissions: 4

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000059022	SCV005078719	uncertain significance	not provided	2023-12-11	criteria provided, single submitter	clinical testing	Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 19652879, 16835901, 15953011)
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV004799775	SCV005422292	pathogenic	Hereditary factor XI deficiency disease	2024-10-30	criteria provided, single submitter	clinical testing	Variant summary: F11 c.1853T>G (p.Ile618Ser), also reported as I600S, results in a non-conservative amino acid change located in the Serine proteases, trypsin domain (IPR001254) of the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 8e-06 in 251404 control chromosomes. c.1853T>G has been reported in the literature in the heterozygous state in 2 individuals and in the homozygous state in 1 individual affected with Hereditary factor XI deficiency disease (example, Mitchell_2005, Hill_2005). These data indicate that the variant is likely to be associated with disease. At least one publication reports experimental evidence evaluating an impact on protein function. The most pronounced variant effect results in <10% of normal FXI:C coagulant activity in the homozygous state and 23-60% FXI:C coagulant activity in the heterozygous state (example, Mitchell_2005, Hill_2005), consistent with possible dominant negative effects. The following publications have been ascertained in the context of this evaluation (PMID: 15953011, 16835901). ClinVar contains an entry for this variant (Variation ID: 68190). Based on the evidence outlined above, the variant was classified as pathogenic.
UniProtKB/Swiss-Prot	RCV000059022	SCV000090543	not provided	not provided		no assertion provided	not provided
PreventionGenetics, part of Exact Sciences	RCV003905028	SCV004722091	pathogenic	F11-related disorder	2023-11-29	no assertion criteria provided	clinical testing	The F11 c.1853T>G variant is predicted to result in the amino acid substitution p.Ile618Ser. This variant, also referred to as c.1896T>G (p.Ile600Ser), has previously been reported to be causative for Hemophilia C (see patient IDs 033061 and 5964 in Mitchell et al. 2006. PubMed ID: 16835901; family 12 in Hill et al. 2005. PubMed ID: 15953011). In Mitchell et al., patient 033061 was homozygous for the c.1853T>G variant and exhibited <2% normal FXI protein activity compared to patient 5946 which was heterozygous for the variant and exhibited 23% FXI activity. Acquired disease states including liver disease, may also alter FXI activity. This variant is reported in 0.0018% of alleles in individuals of European (Non-Finnish) descent in gnomAD. This variant is interpreted as pathogenic.