Submissions for variant NM_000132.4(F8):c.2167G>A (p.Ala723Thr)

gnomAD frequency: 0.00001  dbSNP: rs137852436

Total submissions: 9

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	RCV001560529	SCV000603510	pathogenic	not provided	2023-11-24	criteria provided, single submitter	clinical testing	The F8 c.2167G>A; p.Ala723Thr variant (rs137852436), also known as Ala704Thr, has been reported in multiple individuals diagnosed with mild to moderate hemophilia A (see link to FVIII database and references therein, Higuchi 1991, Markoff 2009). The variant is reported in the ClinVar database (Variation ID: 10246) and is observed on only 1 allele in the Genome Aggregation Database, indicating it is not a common polymorphism. The alanine at codon 723 is highly conserved, and additional variants at this position (c.2168C>A; p.Ala723Asp and c.2168C>T; p.Ala723Val) have been described in individuals with hemophilia A and are considered pathogenic (see link to FVIII database and references therein). Based on available information, the p.Ala723Thr variant is considered pathogenic. References: Link to Factor VIII variant database: http://www.factorviii-db.org/ Higuchi M et al. Molecular characterization of severe hemophilia A suggests that about half the mutations are not within the coding regions and splice junctions of the factor VIII gene. Proc Natl Acad Sci U S A. 1991 Aug 15;88(16):7405-9. 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.
NIHR Bioresource Rare Diseases, University of Cambridge	RCV000852072	SCV000899597	pathogenic	Hereditary factor IX deficiency disease	2019-02-01	criteria provided, single submitter	research
Illumina Laboratory Services, Illumina	RCV000010959	SCV001451533	pathogenic	Hereditary factor VIII deficiency disease	2019-06-25	criteria provided, single submitter	clinical testing	The F8 c.2167G>A (p.Ala723Thr) variant, which was also previously referred to as p.Ala704Thr, is a missense variant. Across a selection of the available literature, it has been identified in at least four unrelated individuals with mild-to-moderate hemophilia A (Higuchi et al. 1991; Antonarakis et al. 1995; Inaba et al. 2013). For three cases, factor VIII activity was reported as falling within 2-29%. In the fourth case, the lowest FVIII:C level was recorded clinically was 0.034 IU/mL. This variant is reported at a frequency of 0.000053 in the South Asian population of the Genome Aggregation Database, where it is found on a single hemizygous allele. Coverage of this genomic region is good, suggesting the variant is rare. In addition, multiple in silico algorithms predict the variant, which is located in the F5/8 type A2 domain, to have a deleterious effect. Based on this evidence and application of the ACMG criteria, the p.Ala723Thr variant is classified as pathogenic for hemophilia A, FVIII deficiency.
GeneDx	RCV001560529	SCV001782960	pathogenic	not provided	2024-03-27	criteria provided, single submitter	clinical testing	In silico analysis supports that this missense variant does not alter protein structure/function; This variant is associated with the following publications: (PMID: 22883072, 31064749, 27380589, 19473423, 27704658, 18691168, 8547094, 15625837, 11857744, 16972227, 24845853, 23625609, 21645180, 23711237, 11179760, 20331761, 23617593, 32224444, 25550078, 1908096, 9452104, 15921397, 29296726, 33245802, 33706050, 32897612)
Fulgent Genetics, Fulgent Genetics	RCV002490351	SCV002804170	pathogenic	Hereditary factor VIII deficiency disease; Thrombophilia, X-linked, due to factor 8 defect	2022-04-07	criteria provided, single submitter	clinical testing
3billion	RCV000010959	SCV003841986	pathogenic	Hereditary factor VIII deficiency disease	2023-02-23	criteria provided, single submitter	clinical testing	The variant is observed at an extremely low frequency in the gnomAD v2.1.1 dataset (total allele frequency: <0.001%). The variant is located in a mutational hot spot and/or well-established functional domain in which established pathogenic variants have been reported. In silico tool predictions suggest damaging effect of the variant on gene or gene product (REVEL: 0.84; 3Cnet: 0.63). Same nucleotide change resulting in same amino acid change has been previously reported as pathogenic/likely pathogenic with strong evidence (ClinVar ID: VCV000010246 / PMID: 1908096). A different missense change at the same codon (p.Ala723Val) has been reported to be associated with F8 related disorder (PMID: 25854144). Therefore, this variant is classified as Pathogenic according to the recommendation of ACMG/AMP guideline.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000010959	SCV005395480	pathogenic	Hereditary factor VIII deficiency disease	2024-09-17	criteria provided, single submitter	clinical testing	Variant summary: F8 c.2167G>A (p.Ala723Thr) results in a non-conservative amino acid change in 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 5.5e-06 in 181821 control chromosomes. c.2167G>A has been reported in the literature in multiple individuals affected with mild/moderate Hemophilia A (example: Cygan_2016). These data indicate that the variant is very likely to be associated with disease. The following publication has been ascertained in the context of this evaluation (PMID: 27704658). ClinVar contains an entry for this variant (Variation ID: 10246). Based on the evidence outlined above, the variant was classified as pathogenic.
Mayo Clinic Laboratories, Mayo Clinic	RCV001560529	SCV005413474	pathogenic	not provided	2024-09-04	criteria provided, single submitter	clinical testing	PP1_strong, PP3, PM1, PM2, PM6, PS4_moderate
OMIM	RCV000010959	SCV000031186	pathogenic	Hereditary factor VIII deficiency disease	1995-01-01	no assertion criteria provided	literature only