Submissions for variant NM_000132.4(F8):c.1660A>G (p.Ser554Gly)

gnomAD frequency: 0.00001  dbSNP: rs137852419

Total submissions: 8

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
ClinGen Coagulation Factor Deficiency Variant Curation Expert Panel, Clingen	RCV000010939	SCV004363674	pathogenic	Hereditary factor VIII deficiency disease	2024-02-02	reviewed by expert panel	curation	The c.1660A>G (p.Ser554Gly) missense variant has a REVEL score of 0.938 which meets PP3 criteria (threshold >0.6). This variant is present in 1 hemizygote in gnomAD v2.1.1 and therefore, does not meet criteria for rarity in the population. Fifty-three patients are reported in Johnsen, et. al. 2107 with mild/moderate hemophilia A and the Gly554Ser variant, meeting F8 phenotype criteria for PS4_Very strong and PP4_Moderate (PMID: 29296726). The variant has been found to segregate with hemophilia A across 6 meioses among 4 different families, the PP1 criteria at the strong weight (Internal VCEP contributor). This variant has been reported in individuals who developed an inhibitor to factor replacement therapy and discrepant chromogenic and one-stage factor VIII activity levels (CDC CHAMPS database/Internal VCEP contributor). 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, PP1_Strong, PP4_Moderate, PP3.
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	RCV000727106	SCV000603527	pathogenic	not provided	2023-11-28	criteria provided, single submitter	clinical testing	The F8 c.1660A>G; p.Ser554Gly variant (rs137852419), also known as Ser535Gly for legacy nomenclature, is reported in multiple individuals with mild hemophilia A (FVIII:C: 3-15 percent) (Diamond 1992, Antonarakis 1995, Liu 2002, Factor VIII database). This variant is also reported in ClinVar (Variation ID: 10226). It is only observed on one allele in the Genome Aggregation Database (v2.1.1), indicating it is not a common polymorphism. Computational analyses predict that this variant is deleterious (REVEL: 0.938). Based on available information, this variant is considered to be pathogenic. References: Factor VIII database link: http://www.factorviii-db.org/newstructure.php?aa_first=Ser&mut_id=607&aa_last=Gly Antonarakis SE et al. Molecular etiology of factor VIII deficiency in hemophilia A. Hum Mutat. 1995;5(1):1-22. PMID: 8851012. 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. PMID: 1301932. Liu ML et al. Non-inversion factor VIII mutations in 80 hemophilia A families including 24 with alloimmune responses. Thromb Haemost. 2002 Feb;87(2):273-6. PMID: 11858487.
Eurofins Ntd Llc (ga)	RCV000727106	SCV000705715	likely pathogenic	not provided	2017-01-17	criteria provided, single submitter	clinical testing
GeneDx	RCV000727106	SCV002538903	likely pathogenic	not provided	2022-06-20	criteria provided, single submitter	clinical testing	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: 23711294, 11858487, 19473423, 31361374, 7728145, 1301932)
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000010939	SCV004038380	pathogenic	Hereditary factor VIII deficiency disease	2023-08-08	criteria provided, single submitter	clinical testing	Variant summary: F8 c.1660A>G (p.Ser554Gly) results in a non-conservative amino acid change located in the multicopper oxidase-like, N-terminal domain (IPR011707) of 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 183446 control chromosomes (gnomAD). c.1660A>G (also known as Ser535Gly) has been reported in the literature in multiple individuals affected with mild Factor VIII Deficiency (Hemophilia A) (examples: Diamond_1992 and Miller_2012). 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, 1301932). Three submitters have cited clinical-significance assessments for this variant to ClinVar after 2014. All submitters classified the variant as pathogenic/likely pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic.
Mayo Clinic Laboratories, Mayo Clinic	RCV000727106	SCV005413475	likely pathogenic	not provided	2024-08-16	criteria provided, single submitter	clinical testing	PP3, PP5, PM1, PM2, PS4_moderate
OMIM	RCV000010939	SCV000031166	pathogenic	Hereditary factor VIII deficiency disease	1995-01-01	no assertion criteria provided	literature only
PreventionGenetics, part of Exact Sciences	RCV003934821	SCV004755019	likely pathogenic	F8-related disorder	2024-03-25	no assertion criteria provided	clinical testing	The F8 c.1660A>G variant is predicted to result in the amino acid substitution p.Ser554Gly. This variant, also referred to as p.Ser535Gly using legacy nomenclature, has been reported in individuals with mild to moderate hemophilia A (Diamond et al. 1992. PubMed ID: 1301932; Antonarakis et al. 1995. PubMed ID: 7728145; Liu et al. 2002. PubMed ID: 11858487; F8 database: https://www.factorviii-db.org/index.php). Different missense variants in the same codon (p.Ser554Arg; p.Ser554Cys; p.Ser554Asn) have been reported in individuals with hemophilia A (Feng et al. 2021. PubMed ID: 33245802; Bogdanova et al. 2001. PubMed ID: 11748850; Rydz et al. 2013. PubMed ID: 23913812; F8 database: https://www.factorviii-db.org/index.php). This variant is reported in 0.0036% of alleles in individuals of Latino descent in gnomAD. This variant is interpreted as likely pathogenic.