Submissions for variant NM_000132.4(F8):c.599A>G (p.Glu200Gly)

gnomAD frequency: 0.00001  dbSNP: rs782158761

Total submissions: 4

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
ClinGen Coagulation Factor Deficiency Variant Curation Expert Panel, Clingen	RCV003403227	SCV004363677	pathogenic	Hereditary factor VIII deficiency disease	2024-02-02	reviewed by expert panel	curation	The c.599A>G (p.Glu200Gly) missense variant has a REVEL score of 0.779 which meets PP3 criteria (threshold >0.6). This variant is present in 1 hemizygote in gnomAD v2.1.1 and v3.1 and therefore, does not meet criteria for rarity in the population. At least 9 patients with mild hemophilia A are reported in literature, meeting F8 phenotype criteria for PS4_Very strong and PP4_Moderate (PMID: 29296726, 29388750). Three related individuals were reported in Reitter, et al (PMID: 20431853), and two were specifically mentioned to be uncle and a nephew, which counts as 2 meioses. Additionally, authors of the Boylan, et al. paper informed this VCEP that one of the probands had an affected relative who also has this variant, which is counted as 1 meioses (PMID: 25780857). This gives a total of 3 meioses and meeting PP1_Moderate 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, PP1_Moderate, PP4_Moderate, PP3.
GeneDx	RCV000519065	SCV000617425	uncertain significance	not provided	2019-07-18	criteria provided, single submitter	clinical testing	In silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect; This variant is associated with the following publications: (PMID: 20431853, 29388750)
NIHR Bioresource Rare Diseases, University of Cambridge	RCV000851605	SCV000899356	likely pathogenic	Abnormality of coagulation	2019-02-01	criteria provided, single submitter	research
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV003403227	SCV004122520	pathogenic	Hereditary factor VIII deficiency disease	2023-10-02	criteria provided, single submitter	clinical testing	Variant summary: F8 c.599A>G (p.Glu200Gly) results in a non-conservative amino acid change in the encoded protein sequence and is located near a consensus splice site. Four of five in-silico tools predict a damaging effect of the variant on protein function. Consensus agreement among computation tools predict no significant impact on normal splicing. However, these predictions have yet to be confirmed by functional studies. The variant allele was found at a frequency of 5.5e-06 in 183347 control chromosomes (gnomAD). c.599A>G has been reported in the literature in the hemizygous state in multiple individuals affected with mild Factor VIII Deficiency (Hemophilia A) and in the heterozygous state in at least one female individual who had a mild phenotype (e.g. Miller_2012, Debeljak_2012, Eckhardt_2013, Gebhart_2018). These data indicate that the variant is very likely to be associated with disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. The following publications have been ascertained in the context of this evaluation (PMID: 22958177, 31064749, 23926300, 29388750, 22103590). Two submitters have cited clinical-significance assessments for this variant to ClinVar after 2014. One submitter classified the variant as likely pathogenic, and one submitter classified the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as pathogenic.