Submissions for variant NM_000132.4(F8):c.6679G>A (p.Ala2227Thr)

dbSNP: rs1342196860

Total submissions: 3

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV001265079	SCV004039509	pathogenic	Hereditary factor VIII deficiency disease	2023-08-15	criteria provided, single submitter	clinical testing	Variant summary: F8 c.6679G>A (p.Ala2227Thr) results in a non-conservative amino acid change located in the second coagulation factor 5/8 type C-terminal domain (IPR000421) 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 183414 control chromosomes (gnomAD). c.6679G>A has been reported in the literature in multiple individuals affected with mild or moderate Factor VIII Deficiency (Hemophilia A) (e.g. Ravanbod_2012, Rydz_2013, Chen_2021, Johnsen_2017, Johnsen_2022). These data indicate that the variant is very 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: 22117735, 23913812, 33706050, 29296726, 35770352). One submitter has cited clinical-significance assessments for this variant to ClinVar after 2014 and has classified the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic.
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	RCV003738025	SCV004565130	pathogenic	not provided	2023-06-23	criteria provided, single submitter	clinical testing	The F8 c.6679G>A; p.Ala2227Thr variant (rs1342196860) is reported in the literature in multiple individuals affected with mild to moderate hemophilia A (see F8 database and references therein, Ravanbod 2012, Rydz 2014). This variant is also reported in ClinVar (Variation ID: 973794) and is absent from the Genome Aggregation Database, indicating it is not a common polymorphism. Computational analyses predict that this variant is deleterious (REVEL: 0.95). Based on available information, this variant is considered to be pathogenic. References: Link to Factor VIII variant database: https://f8-db.eahad.org/index.php Ravanbod S et al. Identification of 123 previously unreported mutations in the F8 gene of Iranian patients with haemophilia A. Haemophilia. 2012 May;18(3):e340-6. PMID: 22117735. Rydz N et al. The Canadian "National Program for hemophilia mutation testing" database: a ten-year review. Am J Hematol. 2013 Dec;88(12):1030-4. Erratum in: Am J Hematol. 2014 Jun;89(6):669. PMID: 23913812.
Angelo Bianchi Bonomi Hemophilia and Thrombosis Center, Fondazione IRCCS Ca Granda Ospedale Maggiore Policlinico	RCV001265079	SCV001424862	pathogenic	Hereditary factor VIII deficiency disease	2019-06-01	no assertion criteria provided	clinical testing