Submissions for variant NM_000132.4(F8):c.979C>G (p.Leu327Val)

dbSNP: rs1603435395

Total submissions: 4

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
ClinGen Coagulation Factor Deficiency Variant Curation Expert Panel, Clingen	RCV003235389	SCV004363651	pathogenic	Hereditary factor VIII deficiency disease	2024-02-02	reviewed by expert panel	curation	The c.979C>G (p.Leu327Val) variant is absent from males in population databases (gnomAD v2.1.1/gnomAD v3) meeting PM2_Supporting. This missense variant has a REVEL score of 0.657 (>0.6) and meets criteria for PP3. At least 8 probands reported with mild hemophilia A (PMID: 18691168, PMID: 11857744, PMID: 29296726, PMID: 31064749, PMID: 20860608 and internal VCEP data) meeting F8 phenotype 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/F9: PS4_Very strong, PP3, PM2_Supporting.
NIHR Bioresource Rare Diseases, University of Cambridge	RCV000851921	SCV000900003	pathogenic	Hereditary factor IX deficiency disease	2019-02-01	criteria provided, single submitter	research
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV003235389	SCV003934290	likely pathogenic	Hereditary factor VIII deficiency disease	2023-05-30	criteria provided, single submitter	clinical testing	Variant summary: F8 c.979C>G (p.Leu327Val) results in a conservative amino acid change located in the Multicopper oxidase, second cupredoxin domain (IPR001117) of the encoded protein sequence. Three of five in-silico tools predict a benign effect of the variant on protein function. The variant was absent in 183107 control chromosomes. c.979C>G has been reported in the literature in individuals affected with features of mild Factor VIII Deficiency (Haemophilia A) and in settings of comprehensive multigene panel testing for bleeding, thrombotic, and platelet disorders (example, Cutler_2002, Green_2008, Siddiq_2011, Miller_2012, Downes_2019). These data indicate that the variant is likely to be associated with disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. p.Leu327Arg; p.Leu327Gln and p.Leu327Pro have been listed in association with Haemophilia A in HGMD database. The following publications have been ascertained in the context of this evaluation (PMID: 11857744, 31064749, 18691168, 22103590, 20860608). One clinical diagnostic laboratory has submitted clinical-significance assessments for this variant to ClinVar after 2014 and classified the variant as pathogenic. Based on the evidence outlined above, the variant was classified as likely pathogenic.
PreventionGenetics, part of Exact Sciences	RCV003396339	SCV004102906	likely pathogenic	F8-related disorder	2023-08-31	criteria provided, single submitter	clinical testing	The F8 c.979C>G variant is predicted to result in the amino acid substitution p.Leu327Val. This variant (also reported as L308V) has reported in individuals with mild Hemophilia A (Table 3, Cutler et al. 2002. PubMed ID: 11857744; ; segregation with an affected uncle in Siddiq et al. 2011. PubMed ID: 20860608; Supplemental Table 3, Downes et al. 2019. PubMed ID: 31064749). This variant has not been reported in a large population database (http://gnomad.broadinstitute.org), indicating this variant is rare. This variant is interpreted as likely pathogenic.