Submissions for variant NM_000132.4(F8):c.935T>C (p.Phe312Ser)

Minimum review status:		Collection method:
Minimum conflict level: Report conflict between different conditions
		ClinVar version:

Total submissions: 5

Download table as spreadsheet

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
NIHR Bioresource Rare Diseases, University of Cambridge	RCV000852250	SCV000899989	pathogenic	Hereditary factor IX deficiency disease	2019-02-01	criteria provided, single submitter	research
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	RCV003656098	SCV001157924	pathogenic	not provided	2023-06-19	criteria provided, single submitter	clinical testing	The F8 c.935T>C; p.Phe312Ser variant (rs137852405), also known as p.Phe293Ser in traditional nomenclature, is reported in the literature in numerous individuals affected with mild hemophilia A (Higuchi 1991, Johnsen 2017, Liu 1998, Miller 2012). This variant is reported in ClinVar (Variation ID: 10196), but it is absent from the Genome Aggregation Database indicating it is not a common polymorphism. The phenylalanine at codon 312 is moderately conserved, and modeling approaches suggest this variant disrupts tertiary structure and hydrogen bonding patterns in the mature protein (Liu 1998, Markoff 2009). Further, this variant occurs in a domain involved in interaction with the chaperone protein BiP and cellular studies suggest it results in impaired secretion (Swaroop 1997). Based on available information, the p.Phe312Ser variant is considered to be pathogenic. References: 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. PMID: 1908096. Johnsen JM et al. Novel approach to genetic analysis and results in 3000 hemophilia patients enrolled in the My Life, Our Future initiative. Blood Adv. 2017 May 18;1(13):824-834. PMID: 29296726. Liu M et al. A domain mutations in 65 haemophilia A families and molecular modelling of dysfunctional factor VIII proteins. Br J Haematol. 1998 Dec;103(4):1051-60. PMID: 9886318. 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. Miller CH et al. F8 and F9 mutations in US haemophilia patients: correlation with history of inhibitor and race/ethnicity. Haemophilia. 2012 May;18(3):375-82. PMID: 22103590. Swaroop M et al. Mutagenesis of a potential immunoglobulin-binding protein-binding site enhances secretion of coagulation factor VIII. J Biol Chem. 1997 Sep 26;272(39):24121-4. PMID: 9305856.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000010909	SCV004122097	pathogenic	Hereditary factor VIII deficiency disease	2023-10-25	criteria provided, single submitter	clinical testing	Variant summary: F8 c.935T>C (p.Phe312Ser) results in a non-conservative amino acid change in the encoded protein sequence. Four of five in-silico tools predict a damaging effect of the variant on protein function. The variant was absent in 183329 control chromosomes (gnomAD). c.935T>C has been reported in the literature in multiple individuals affected with Factor VIII Deficiency (Hemophilia A) (examples: Higuchi_1991, Miller_2012, Downes_2019). 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: 31064749, 22103590, 1908096). Two submitters have cited clinical-significance assessments for this variant to ClinVar after 2014. All submitters classified the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic.
GeneDx	RCV003656098	SCV005201774	likely pathogenic	not provided	2023-09-06	criteria provided, single submitter	clinical testing	Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 19473423, 31064749, 1908096, 31361374)
OMIM	RCV000010909	SCV000031136	pathogenic	Hereditary factor VIII deficiency disease	1991-08-15	no assertion criteria provided	literature only

The information on this website is not intended for direct diagnostic use or medical decision-making without review by a genetics professional. Individuals should not change their health behavior solely on the basis of information contained on this website. Neither the University of Utah nor the National Institutes of Health independently verfies the submitted information. If you have questions about the information contained on this website, please see a health care professional.