Total submissions: 2
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| ARUP Laboratories, |
RCV000757250 | SCV000885400 | pathogenic | not provided | 2023-11-13 | criteria provided, single submitter | clinical testing | The F8 c.575T>C; p.Ile192Thr variant, also known as p.Ile173Thr, is reported in the literature in several individuals with mild hemophilia A (Bogdanova 2007, Green 2008, F8 database and references therein). Functional assays of patient samples suggest clotting activity 18-33% of wildtype (F8 database and references therein). This variant is absent from the Genome Aggregation Database, indicating it is not a common polymorphism. The isoleucine at codon 192 is highly conserved, and computational analyses predict that this variant is deleterious (REVEL: 0.944). Additionally, other amino acid substitutions at this codon (p.Ile192Asn) and in nearby amino acids (p.Gly190Asp, p.Gly193Arg, p.Gly193Glu) have been reported in individuals with hemophilia A and are considered pathogenic (Lu 2018, F8 database and references therein). Based on available information, the p.Ile192Thr variant is considered pathogenic. References: F8 database: http://www.factorviii-db.org Bogdanova N et al. Spectrum of molecular defects and mutation detection rate in patients with mild and moderate hemophilia A. Hum Mutat. 2007 Jan;28(1):54-60. PMID: 16972227. Green PM et al. Haemophilia A mutations in the UK: results of screening one-third of the population. Br J Haematol. 2008 Oct;143(1):115-28. PMID: 18691168. Lu Y et al. Spectrum and origin of mutations in sporadic cases of haemophilia A in China. Haemophilia. 2018 Mar;24(2):291-298. PMID: 29381227. |
| Women's Health and Genetics/Laboratory Corporation of America, |
RCV004702392 | SCV005204901 | pathogenic | Hereditary factor VIII deficiency disease | 2024-06-26 | criteria provided, single submitter | clinical testing | Variant summary: F8 c.575T>C (p.Ile192Thr) results in a non-conservative amino acid change located in the Multicopper oxidase-like, N-terminal domain (IPR011707) 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 183353 control chromosomes (gnomAD). c.575T>C has been reported in the literature in multiple individuals affected with Factor VIII Deficiency (Hemophilia A; e.g. Bogdanova_2007, Green_2008, Santacroce_2008, Miller_2017, Johnsen_2017). These data indicate that the variant is very likely to be associated with disease. The following publications have been ascertained in the context of this evaluation (PMID: 16972227, 29296726, 18691168, 18217193, 22103590). ClinVar contains an entry for this variant (Variation ID: 618637). Based on the evidence outlined above, the variant was classified as pathogenic. |