ClinVar Miner

Submissions for variant NM_000132.4(F8):c.2215G>A (p.Glu739Lys)

gnomAD frequency: 0.00002  dbSNP: rs28937285
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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 RCV000010960 SCV004363660 pathogenic Hereditary factor VIII deficiency disease 2024-02-02 reviewed by expert panel curation The c.2215G>A (p.Glu739Lys) missense variant is absent from males in both gnomAD v2.1.1 and v3.1.1, meeting the PM2_Supporting criteria. The variant has a REVEL score of 0.614 (>0.6), meeting PP3 criteria. At least 13 patients with mild hemophilia A are reported in the literature and internal laboratory data meeting F8 phenotype criteria (PMID: 24452774, 23711237, 21166991, 8547094, 16972227), which meets the PS4_Very strong and PP4_Moderate criteria. This variant has been labeled as an inverse discrepant variant, where the one-stage assays show lower factor VIII levels than the two-stage, or chromogenic, assays (EAHAD database; PMID: 32232366). There were multiple related individuals across 6 different families reported that were genotyped, but their specific relation was not stated, so the PP1 was capped at the moderate weight to be conservative (PMID: 24452774). In-vitro assays in COS-1 cells show FVIII-Glu739Lys results in lower FVIII:C in the mild range, as observed in patients with this variant and hemophilia A (PMID: 30997536). 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, PP1_Moderate, PP4_Moderate, PP3, PM2_Supporting.
OMIM RCV000010960 SCV000031187 pathogenic Hereditary factor VIII deficiency disease 1995-01-01 no assertion criteria provided literature only
PreventionGenetics, part of Exact Sciences RCV004745152 SCV005362704 likely pathogenic F8-related disorder 2024-04-03 no assertion criteria provided clinical testing The F8 c.2215G>A variant is predicted to result in the amino acid substitution p.Glu739Lys. This variant (aka. p.Glu720Lys) has been reported in multiple individuals with hemophilia A (Schwaab et al. 1995. PubMed ID: 8547094; Factor VIII (F8) Gene Variant Database: https://www.factorviii-db.org/index.php). This variant is reported in 0.0092% of alleles in individuals of European (Non-Finnish) descent in gnomAD. This variant is interpreted as likely pathogenic.

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