ClinVar Miner

Submissions for variant NM_000132.4(F8):c.923C>T (p.Ser308Leu)

dbSNP: rs137852404
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Total submissions: 3
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
ClinGen Coagulation Factor Deficiency Variant Curation Expert Panel, Clingen RCV000010908 SCV005061637 pathogenic Hereditary factor VIII deficiency disease 2024-05-09 reviewed by expert panel curation The c.923C>T (NM_000132.3) variant in F8 is a missense variant predicted to cause substitution of Serine by Leucine at amino acid 308 (p.Ser308Leu). This variant is absent from gnomAD v2.1.1 and v3.1.2 (PM2_Supporting). This variant has been reported in at least 21 probands meeting the hemophilia A phenotype criteria specified by the Coagulation Factor Deficiency VCEP. Several probands are reported with mild hemophilia A (>4) and VWD 2N exclusion was reported in at least 2 probands (PS4_VeryStrong; PMID: 10338101, 8759905, 19448530, 8449505, 18691168, 15921397, 19719828, 16972227, 18371166, 28674365, 30046696, 31026269, 21645180, 24845853, 22958177, 17445092). This variant has been identified as a de novo occurrence with confirmed maternal relationship (X-linked condition) in 1 male patient with severe hemophilia A (2 points per the ClinGen SVI PS2/PM6 table; PS2; PMID: 1837116). The variant has been reported to segregate with mild hemophilia A in 2 affected siblings from 1 family (PP1; PMID: 19448530). This variant is absent from gnomAD v2.1.1 and v3.1.2 (PM2_Supporting). The computational predictor REVEL gives a score of 0.800, which is above the threshold of 0.6, evidence that correlates with impact to F8 function (PP3). This variant has also been associated with discrepant factor VIII activity levels, with lower chromogenic factor VIII lab values (PMID: 32232366). In summary, this variant meets the criteria to be classified as pathogenic for X-linked recessive hemophilia A based on the ACMG/AMP criteria applied, as specified by the ClinGen Coagulation Factor Deficiency VCEP: PS4_VeryStrong, PS2, PP1, PP3, PM2_Supporting. (ClinGen Coagulation Factor Deficiency Expert Panel Specifications to the ACMG/AMP Variant Interpretation Guidelines for F8 Version 1.0.0., Released 10/5/2023).
PreventionGenetics, part of Exact Sciences RCV003415685 SCV004115815 pathogenic F8-related disorder 2022-12-01 criteria provided, single submitter clinical testing The F8 c.923C>T variant is predicted to result in the amino acid substitution p.Ser308Leu. This variant is also described using legacy nomenclature as p.Ser289Leu, has been reported in multiple individuals with Hemophilia A (McGinniss et al. 1993. PubMed ID: 8449505; Bogdanova et al. 2007. PubMed ID: 16972227. Table S1; Castaman et al. 2009. PubMed ID: 19719828; Saito et al. 2017. PubMed ID: 28674365; F8 database: http://www.factorviii-db.org/advance_search.php). 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 pathogenic.
OMIM RCV000010908 SCV000031135 pathogenic Hereditary factor VIII deficiency disease 1993-02-01 no assertion criteria provided literature only

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