Submissions for variant NM_000132.4(F8):c.6532C>T (p.Arg2178Cys)

dbSNP: rs137852464

Total submissions: 6

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	RCV003103985	SCV002049465	pathogenic	not provided	2022-06-13	criteria provided, single submitter	clinical testing	The F8 c.6532C>T; p.Arg2178Cys variant (rs137852464), also known as R2159C, is reported in the literature in multiple individuals and families affected with mild to moderate hemophilia A (see link to FVIII database and references therein, Markoff 2009). This variant is also reported in ClinVar (Variation ID: 10318). It is absent from the Genome Aggregation Database, indicating it is not a common polymorphism. The arginine at codon 2178 is highly conserved, and computational analyses predict that this variant is deleterious (REVEL: 0.875). Additionally, other amino acid substitutions at this codon (Leu, His, Lys) have been reported in individuals with mild hemophilia A and are considered pathogenic (FVIII database, Markoff 2009). Based on available information, the p.Arg2178Cys variant is considered to be pathogenic. References: Link to FVIII database: http://www.factorviii-db.org/ Markoff A et al. Combined homology modelling and evolutionary significance evaluation of missense mutations in blood clotting factor VIII to highlight aspects of structure and function. Haemophilia. 2009 Jul;15(4):932-41. PMID: 19473423
Genetics and Molecular Pathology, SA Pathology	RCV000011031	SCV004175453	pathogenic	Hereditary factor VIII deficiency disease	2021-10-27	criteria provided, single submitter	clinical testing
New York Genome Center	RCV000011031	SCV005044080	pathogenic	Hereditary factor VIII deficiency disease	2023-03-10	criteria provided, single submitter	clinical testing	The hemizygous, maternally inherited c.6532C>T, p.(Arg2178Cys) variant (also called R2159C, or p.Arg2159Cys) identified in the F8 gene of this fetus has been reported in many affected individuals and is typically associated with mild hemophilia A [PMID:1924291, 11754115, 17445092, 21771207, others]. Decreased Factor VIII activity has been reported in a male with the c.6532C>T, p.(Arg2178Cys) variant [PMID:1924291]. This variant is reported in ClinVar as Pathogenic (VarID:10318; 1 star, 3 submissions, no conflicts), and two different amino acid changes at the same amino acid position, p.Arg2178Leu (VarID:10314) and p.Arg2178His (VarID:10319) are also reported as Likely Pathogenic/Pathogenic. In silico algorithm REVEL predicts this variant to be damaging to protein function (Score: 0.875). Given the available evidence the hemizygous, maternally inherited c.6532C>T, p.(Arg2178Cys) variant identified in the F8 gene is reported as Pathogenic.
Mayo Clinic Laboratories, Mayo Clinic	RCV003103985	SCV005413463	likely pathogenic	not provided	2024-04-10	criteria provided, single submitter	clinical testing	PP1, PP3, PM1, PM2_moderate, PM5, PS4_moderate
OMIM	RCV000011031	SCV000031258	pathogenic	Hereditary factor VIII deficiency disease	1995-01-01	no assertion criteria provided	literature only
Angelo Bianchi Bonomi Hemophilia and Thrombosis Center, Fondazione IRCCS Ca Granda Ospedale Maggiore Policlinico	RCV000011031	SCV001424874	pathogenic	Hereditary factor VIII deficiency disease	2019-06-01	no assertion criteria provided	clinical testing