Submissions for variant NM_000132.4(F8):c.3169G>A (p.Glu1057Lys)

gnomAD frequency: 0.00014  dbSNP: rs28933673

Total submissions: 9

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
UCLA Clinical Genomics Center, UCLA	RCV000010964	SCV000255367	likely pathogenic	Hereditary factor VIII deficiency disease	2013-04-16	criteria provided, single submitter	clinical testing
Soonchunhyang University Bucheon Hospital, Soonchunhyang University Medical Center	RCV000010964	SCV000267308	likely pathogenic	Hereditary factor VIII deficiency disease	2016-03-18	criteria provided, single submitter	reference population
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	RCV000010964	SCV000731569	uncertain significance	Hereditary factor VIII deficiency disease	2022-11-03	criteria provided, single submitter	clinical testing	The p.Glu1057Lys (NM_000132.3 c.3169G>A) variant in F8 has been reported hemizygously in three males with Hemophilia A and low factor VIII levels, though one of these individuals carried a second pathogenic variant (Higuchi 1991, Chan 1996, Huang 2009). This variant has also been reported in ClinVar (Variation ID#10251). This variant has been identified in 0.7% (95/13902) of East Asian chromosomes, including 1 homozygote and 29 hemizygotes, by the Genome Aggregation Database (gnomAD, http://gnomad.broadinstitute.org; dbSNP rs28933673). In vitro functional studies provide some evidence that the p.Glu1057Lys variant may impact protein function (Pahl 2014); however, these types of assays may not accurately represent biological function. In summary, while there is some suspicion for a pathogenic role, the clinical significance of the p.Glu1057Lys variant is uncertain.
Mendelics	RCV002247322	SCV002519668	pathogenic	Thrombophilia, X-linked, due to factor 8 defect	2022-05-04	criteria provided, single submitter	clinical testing
Victorian Clinical Genetics Services, Murdoch Childrens Research Institute	RCV000010964	SCV002769093	uncertain significance	Hereditary factor VIII deficiency disease	2022-02-02	criteria provided, single submitter	clinical testing	Based on the classification scheme VCGS_Germline_v1.3.4, this variant is classified as VUS-3B. Following criteria are met: 0102 - Loss of function is a known mechanism of disease in this gene and is associated with haemophilia A (MIM#306700). (I) 0109 - This gene is associated with X-linked recessive disease. (I) 0200 - Variant is predicted to result in a missense amino acid change from glutamic acid to lysine. (I) 0253 - This variant is hemizygous. (I) 0304 - Variant is present in gnomAD (v2) <0.01 for a recessive condition (71 heterozygotes, 1 homozygote, 36 hemizygotes). (SP) 0502 - Missense variant with conflicting in silico predictions and uninformative conservation. (I) 0600 - Variant is located in the annotated B domain (PMID: 24108539). (I) 0705 - No comparable missense variants have previous evidence for pathogenicity. (I) 0808 - Previous reports of pathogenicity for this variant are conflicting. It has been reported in at least three individuals with haemophilia A (PMIDs: 1924291, 19719548, 30913330). It has also been reported as polymorphism in a haemophilia A cohort, and as hemizygous in an individual with haemophilia B (PMIDs: 18479430, 29296726). It has been reported as both likely pathogenic and uncertain significance in ClinVar. (I) 0905 - No published segregation evidence has been identified for this variant. (I) 1010 - Functional evidence for this variant is inconclusive. Authors of a functional study using transfected HEK cells described that the variant protein had mildly decreased factor VIII activity and significantly reduced thermostability (PMID: 24108539), however their raw data was incomplete and not convincing. (I) 1208 - Inheritance information for this variant is not currently available in this individual. (I) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000601703	SCV004222923	uncertain significance	not specified	2023-11-03	criteria provided, single submitter	clinical testing	Variant summary: F8 c.3169G>A (p.Glu1057Lys) results in a conservative amino acid change in the encoded protein sequence. Three of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 0.00059 in 182664 control chromosomes, predominantly at a frequency of 0.0071 within the East Asian subpopulation in the gnomAD database, including 1 homozygote and 36 hemizygotes across the subpopulations. This frequency is not significantly higher than estimated for a pathogenic variant in F8 causing Factor VIII Deficiency (Hemophilia A) (0.00059 vs 0.0098), allowing no conclusion about variant significance. c.3169G>A has been reported in the literature in individuals affected with Factor VIII Deficiency (Hemophilia A) without strong evidence of causality (e.g. Higuchi_1991b, Chan_1996, Hwang_2009, Luu_2019, Li_2020, Chen_2021). These reports do not provide unequivocal conclusions about association of the variant with Factor VIII Deficiency (Hemophilia A). At least one publication reports experimental evidence evaluating an impact on protein function, finding that the variant results in reduced FVIII activity and antigen values in HEK293T cells (Pahl_2014). The following publications have been ascertained in the context of this evaluation (PMID: 1924291, 8639447, 19719548, 29296726, 32190902, 34272389, 33706050, 33245802, 35770352, 30913330, 24108539). Four submitters have cited clinical-significance assessments for this variant to ClinVar after 2014, and classified it as uncertain significance (n=2), likely pathogenic (n=1) or pathogenic (n=1). Based on the evidence outlined above, the variant was classified as VUS-possibly pathogenic.
Institute of Immunology and Genetics Kaiserslautern	RCV000010964	SCV005382127	likely pathogenic	Hereditary factor VIII deficiency disease	2022-08-05	criteria provided, single submitter	clinical testing	ACMG Criteria: PS3, PP2, PP3, PP5; Variant was found in heterozygous state.
Mayo Clinic Laboratories, Mayo Clinic	RCV004791213	SCV005411528	uncertain significance	not provided	2024-06-28	criteria provided, single submitter	clinical testing	BS1, BS2, PS3_supporting, PS4_moderate
OMIM	RCV000010964	SCV000031191	pathogenic	Hereditary factor VIII deficiency disease	1993-02-01	no assertion criteria provided	literature only