Submissions for variant NM_000132.4(F8):c.396A>C (p.Glu132Asp)

gnomAD frequency: 0.00018  dbSNP: rs137852388

Total submissions: 9

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
CeGaT Center for Human Genetics Tuebingen	RCV001529373	SCV001962683	uncertain significance	not provided	2023-08-01	criteria provided, single submitter	clinical testing	F8: PM1, PM5
Mendelics	RCV002247319	SCV002519682	pathogenic	Thrombophilia, X-linked, due to factor 8 defect	2022-05-04	criteria provided, single submitter	clinical testing
ISTH-SSC Genomics in Thrombosis and Hemostasis, KU Leuven, Center for Molecular and Vascular Biology	RCV002280860	SCV002569313	likely benign	Hemorrhage		criteria provided, single submitter	clinical testing
Genetics and Molecular Pathology, SA Pathology	RCV000010884	SCV002761472	likely benign	Hereditary factor VIII deficiency disease	2020-08-31	criteria provided, single submitter	clinical testing	The F8:c.396A>C variant is predicted to result in a missense change from glutamic acid to aspartic acid at amino acid 132 (p.Glu132Asp, formerly known as p.Glu113Asp). This variant has an allele frequency of 0.0003158 in non-Finnish European controls (gnomAD 2.1.2). This is significantly higher than expected for a pathogenic variant, given the incidence of haemophilia A (1/4000 males, PMID 32497379), and the proportion of symptomatic haemophilia A attributable to missense variation (17% severe and 81% non-severe haemophilia A, PMID 35770352) (BS1). This variant has been seen in cis to p.Arg612Cys (formerly p.Arg593Cys) in 22 Slovenian patients with Haemophilia A. In this study, an affected patient was identified with the less common p.Arg612Cys alone, but no patients had only F8:c.396A>C. This variant was also reported in cis to a frameshift variant in severe HA (PMID 11442643) (BP2). F8:c.396A>C has been reported in five patients with haemophilia A, prior to the availability of allele frequency databases (PMID 7984443, 19473423, 17445092, 15921397, 16173970), with 5 further unpublished cases on the EAHAD database. However, studies after the development of ACMG variant classification consider this variant benign or of unknown significance (eg. PMID 36007526, 34272389). In a multicentre analysis of US haemophilia treatment centres, with 8976 haemophilia A cases and 2358 haemophilia B cases, this variant was detected in haemophilia B patients and regarded as non-reportable (PMID 35770352). Locally, this variant was identified in two hemizygous males with no clinical or biochemical evidence of haemophilia A (BP5).
Fulgent Genetics, Fulgent Genetics	RCV002496321	SCV002808980	likely pathogenic	Hereditary factor VIII deficiency disease; Thrombophilia, X-linked, due to factor 8 defect	2021-10-29	criteria provided, single submitter	clinical testing
Center For Human Genetics And Laboratory Diagnostics, Dr. Klein, Dr. Rost And Colleagues	RCV000010884	SCV004229140	uncertain significance	Hereditary factor VIII deficiency disease	2024-01-08	criteria provided, single submitter	clinical testing
PreventionGenetics, part of Exact Sciences	RCV003952352	SCV004767543	pathogenic	F8-related disorder	2024-01-29	criteria provided, single submitter	clinical testing	The F8 c.396A>C variant is predicted to result in the amino acid substitution p.Glu132Asp. Using legacy nomenclature, this variant is also referred to as p.Glu113Asp). This variant has been reported to be causative for Hemophilia A (Freson et al. 1998. PubMed ID: 9603440; Markoff et al. 2009. PubMed ID: 19473423; Trampuš Bakija et al. 2015. PubMed ID: 26057490; Supplemental Table 2, Baz et al. 2021. PubMed ID: 34272389). Of note, another variant impacting the same amino acid has also been reported in individuals with Hemophilia A [c.395A>C (p.Glu132Ala, aka p.Glu113Ala using legacy nomenclature), Repesse et al. 2007. PubMed ID: 17445092]. This variant is reported in 0.034% of alleles in individuals of European (Non-Finnish) descent in gnomAD. This variant is interpreted as pathogenic.
Victorian Clinical Genetics Services, Murdoch Childrens Research Institute	RCV000010884	SCV005086160	likely benign	Hereditary factor VIII deficiency disease	2023-07-17	criteria provided, single submitter	clinical testing	Based on the classification scheme VCGS_Germline_v1.3.4, this variant is classified as Likely benign. The following criteria are met: 0102 - Loss of function is a known mechanism of disease in this gene and is associated with hemophilia A (MIM#306700). (I) 0109 - This gene is associated with X-linked recessive disease. (I) 0115 - Variants in this gene are known to have variable expressivity. Individuals with hemophilia A vary in severity ranging from mild to severe depending on the plasma levels of coagulation factor VIII (OMIM). (I) 0200 - Variant is predicted to result in a missense amino acid change from glutamic acid to aspartic acid. (I) 0251 - This variant is heterozygous. (I) 0308 - Population frequency for this variant is out of keeping with known incidence of Hemophilia A. This variant is present in gnomAD (v2: 1 homozygote, 12 hemizygotes) and has been identified in a number of unaffected hemizygotes in a newborn screening study of ~454000 UK biobank subjects (PMID:36007526). (SB) 0503 - Missense variant consistently predicted to be tolerated by multiple in silico tools or not conserved in placental mammals with a minor amino acid change. (SB) 0600 - Variant is located in the annotated A1 domain (UniProt). (I) 0705 - No comparable missense variants have previous evidence for pathogenicity. The variant p.(Glu132Ala) has a larger amino acid change (Grantham score = 107) and has been reported once in a patient with mild hemophilia A (PMID: 17445092). (I) 0808 - Previous reports of pathogenicity for this variant are conflicting. This variant has been classified as pathogenic, likely pathogenic and likely benign in ClinVar by other clinical laboratories. In the literature, it has been reported in families with mild hemophilia A (PMID: 22958177; 15921397) however in other families it has been reported in cis with other known pathogenic F8 variants where the pathogenicity of this variant could not be determined (PMID: 9603440; 11442643; 26057490). Internal data shows that individuals with this variant had mildly reduced to normal levels of factor VIII and none reported any history of excessive bleeding. (I) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign
OMIM	RCV000010884	SCV000031111	pathogenic	Hereditary factor VIII deficiency disease	1995-01-01	no assertion criteria provided	literature only