Submissions for variant NM_000128.4(F11):c.1724C>T (p.Ser575Leu)

gnomAD frequency: 0.00001  dbSNP: rs281875250

Total submissions: 3

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Knight Diagnostic Laboratories, Oregon Health and Sciences University	RCV000454166	SCV000538024	likely pathogenic	Hereditary factor XI deficiency disease	2016-03-30	criteria provided, single submitter	clinical testing	The c.1724C>T (p.Ser575Leu) missense variant in the F11 gene has been previously reported in three unrelated individuals affected with CRM+ Factor XI deficiency. Consistent with the CRM+ type Factor XI deficiency, these individuals had reduced coagulation activity but normal antigen levels (FXI:Ag = 60-86 UI/dL) indicating there was normal level of protein present in the plasma, but reduced enzyme function (Guéguen et al., 2012). The individual who was homozygous for this variant had lower coagulation activity (FXI C:1 UI/dL) compared with the two individuals who were heterozygous for this variant (FXI C: 28 UI/dL and 38 UI/dL respectively; normal range 70-15 IU/dL). The c.1724C>T (p.Ser575Leu) variant is located in the active site of the FXI protein, which would be predicted to inhibit the serine protease function of the protein. This variant is absent from the population databases (Exome Sequencing Project; 1000 Genomes; ExAC). Multiple in silico algorithms predict a deleterious effect (GERP = 5.05; CADD = 16.48; PolyPhen = 1.0; SIFT = 0). Therefore, this collective evidence supports the classification of the c.1724C>T (p.Ser575Leu) as a Likely pathogenic variant for Factor XI Deficiency.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000454166	SCV005185848	likely pathogenic	Hereditary factor XI deficiency disease	2024-05-14	criteria provided, single submitter	clinical testing	Variant summary: F11 c.1724C>T (p.Ser575Leu) results in a non-conservative amino acid change located in the trypsin domain (IPR001254), affecting the serine active site (IPR033116) of the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant was absent in 251412 control chromosomes (gnomAD). c.1724C>T has been reported in the literature in individuals affected with Hereditary factor XI deficiency disease (e.g. Gueguen_2012, Preisler_2021), where heterozygous individuals had moderate F11 deficiency, while a reported homozygous individual had severe F11 deficiency. These data indicate that the variant is likely to be associated with disease. 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: 33477601, 22159456). ClinVar contains an entry for this variant (Variation ID: 68187). Based on the evidence outlined above, the variant was classified as likely pathogenic.
UniProtKB/Swiss-Prot	RCV000059019	SCV000090540	not provided	not provided		no assertion provided	not provided