Submissions for variant NM_000132.4(F8):c.5822A>G (p.Asn1941Ser)

dbSNP: rs28933682

Total submissions: 6

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
ClinGen Coagulation Factor Deficiency Variant Curation Expert Panel, Clingen	RCV000011007	SCV004363666	pathogenic	Hereditary factor VIII deficiency disease	2024-02-02	reviewed by expert panel	curation	The c.5822A>G (p.Asn1941Ser) variant is completely absent from gnomAD v2.1.1 and v3.1.1, which meets PM2_Supporting. This missense variant has a REVEL score of 0.943 (>0.6) and meets criteria for PP3. At least 80 probands have been reported in the literature and from internal laboratory data who meet the F8 phenotype criteria meeting thresholds for PS4_Very strong (>8 probands) and PP4_Moderate. Two brothers have been reported with severe hemophilia A, which meets the PP1 criteria (PMID: 15996930). Functional evidence from PMID: 21217077 shows that the variant results in a secretory defect based on barely detectable levels of antigen and activity when expressed in BHK cells, which meets PS3 criteria. In summary, this variant meets criteria to be classified as pathogenic. ACMG/AMP criteria applied, as specified by the Coagulation Factor Deficiency Variant Curation Expert Panel for F8: PS4_Very strong, PS3, PM2_Supporting, PP1, PP3.
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	RCV000011007	SCV000603528	pathogenic	Hereditary factor VIII deficiency disease	2021-01-14	criteria provided, single submitter	clinical testing	The F8 c.5822A>G, p.Asn1941Ser variant (rs28933682), also known as Asn1922Ser, has been reported in patients diagnosed with moderate to severe hemophilia A (Astermark 2005, Diamond 2005, Higuchi 1991, Summers 2011, Factor VIII Variant Database and references therein). Functional testing in patients with this variant suggest below 5% of normal activity (Factor VIII Variant Database), and characterization of the variant protein in heterologous cells indicates defective processing, accumulation in the endoplasmic reticulum, decreased F8 secretion (Summers 2011). This variant is absent from general population databases (Exome Variant Server, Genome Aggregation Database), indicating it is not a common polymorphism. The asparagine at residue 1941 is highly conserved, other amino acid substitutions at this codon (Asp, Ile, Lys, Thr) have been reported in individuals with hemophilia A and are considered disease-causing (Factor VIII Variant Database and references therein). Based on available information, the p.Asn1941Ser variant is considered to be pathogenic. References: Factor VIII Variant Database: http://f8-db.eahad.org/ Astermark J et al. The Malmo International Brother Study (MIBS). Genetic defects and inhibitor development in siblings with severe hemophilia A. Haematologica. 2005; 90(7):924-31. Diamond C et al. Amino acid substitutions in conserved domains of factor VIII and related proteins: study of patients with mild and moderately severe hemophilia A. Hum Mutat. 1992; 1(3):248-57. 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; 88(16):7405-9. Summers R et al. Factor VIII A3 domain substitution N1922S results in hemophilia A due to domain-specific misfolding and hyposecretion of functional protein. Blood. 2011; 117(11):3190-8.
Johns Hopkins Genomics, Johns Hopkins University	RCV000011007	SCV002570360	pathogenic	Hereditary factor VIII deficiency disease	2022-08-04	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000011007	SCV004223780	pathogenic	Hereditary factor VIII deficiency disease	2023-11-14	criteria provided, single submitter	clinical testing	Variant summary: F8 c.5822A>G (p.Asn1941Ser) results in a conservative amino acid change located in the Multicopper oxidase, C-terminal domain (IPR011706) of 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 183127 control chromosomes (gnomAD). c.5822A>G has been reported in the literature in multiple individuals affected with Factor VIII Deficiency (Hemophilia A) (examples: Miller_2012 and Chen_2021). 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: 22103590, 33706050). 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.
Mayo Clinic Laboratories, Mayo Clinic	RCV004791214	SCV005413470	pathogenic	not provided	2023-08-23	criteria provided, single submitter	clinical testing	PP3, PM1, PM2_moderate, PS3, PS4_moderate
OMIM	RCV000011007	SCV000031234	pathogenic	Hereditary factor VIII deficiency disease	2011-03-17	no assertion criteria provided	literature only