rs137852404
Variant summary
Our verdict is Pathogenic. Variant got 12 ACMG points: 12P and 0B. PM2PP3PP1PS4PS2
This summary comes from the ClinGen Evidence Repository: 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). LINK:https://erepo.genome.network/evrepo/ui/classification/CA255082/MONDO:0010602/071
Frequency
Consequence
NM_000132.4 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Pathogenic. Variant got 12 ACMG points.
Transcripts
RefSeq
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | Exon rank | TSL | MANE | Protein | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|---|
F8 | ENST00000360256.9 | c.923C>T | p.Ser308Leu | missense_variant | Exon 7 of 26 | 1 | NM_000132.4 | ENSP00000353393.4 | ||
F8 | ENST00000647125.1 | n.*799C>T | non_coding_transcript_exon_variant | Exon 8 of 14 | ENSP00000496062.1 | |||||
F8 | ENST00000647125.1 | n.*799C>T | 3_prime_UTR_variant | Exon 8 of 14 | ENSP00000496062.1 |
Frequencies
GnomAD3 genomes Cov.: 23
GnomAD4 exome AF: 9.11e-7 AC: 1AN: 1097955Hom.: 0 Cov.: 30 AF XY: 0.00 AC XY: 0AN XY: 363363
GnomAD4 genome Cov.: 23
ClinVar
Submissions by phenotype
Hereditary factor VIII deficiency disease Pathogenic:2
Pathogenic, reviewed by expert panel | curation | ClinGen Coagulation Factor Deficiency Variant Curation Expert Panel, Clingen | May 09, 2024 | 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). - |
Pathogenic, no assertion criteria provided | literature only | OMIM | Feb 01, 1993 | - - |
F8-related disorder Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | PreventionGenetics, part of Exact Sciences | Dec 01, 2022 | 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. - |
not provided Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories | Apr 29, 2024 | The F8 c.923C>T, p.Ser308Leu variant (rs137852404), also known as Ser298Leu, is reported in multiple patients diagnosed with mild hemophilia A (Abu-Amero 2008, Bogdanova 2007, Castaman 2009, Fernandez-Lopez 2005, Represse 2007, Rudzki 1996, Strmecki 1999, Factor VIII variant database). Functional studies indicate that the variant is located near the heterotrimer contact surface (Markoff 2009), and increases the rate of dissociation after thrombin activation (Pipe 2001). This variant is also absent from the Genome Aggregation Database, indicating it is not a common polymorphism. The serine at residue 308 is highly conserved, and computational analyses predict that the variant is deleterious (REVEL: 0.80). Based on the above information, the variant is considered to be pathogenic. References: Factor VIII variant database: http://www.factorviii-db.org/ Abu-Amero K et al. Spectrum of factor VIII mutations in Arab patients with severe haemophilia A. Haemophilia. 2008; 14(3):484-8. PMID: 18371166. Bogadnova N et al. Spectrum of molecular defects and mutation detection rate in patients with mild and moderate hemophilia A. Hum Mutat. 2007; 28(1):54-60. PMID: 16972227. Castaman G et al. Molecular and phenotypic determinants of the response to desmopressin in adult patients with mild hemophilia A. J Thromb Haemost. 2009; 7(11):1824-31. PMID: 19719828. Fernandez-Lopez O et al. The spectrum of mutations in Southern Spanish patients with hemophilia A and identification of 28 novel mutations. Haematologica. 2005; 90(5):707-10. PMID: 15921397. Markoff A et al. Combined homology modelling and evolutionary significance evaluation of missense mutations in blood clotting factor VIII to highlight aspects of structure and function. Haemophilia. 2009; 15(4):932-41. PMID: 19473423. Pipe S et al. Hemophilia A mutations associated with 1-stage/2-stage activity discrepancy disrupt protein-protein interactions within the triplicated A domains of thrombin-activated factor VIIIa. Blood. 2001; 97(3):685-91. PMID: 11157485. Repesse Y et al. Factor VIII (FVIII) gene mutations in 120 patients with hemophilia A: detection of 26 novel mutations and correlation with FVIII inhibitor development. J Thromb Haemost. 2007; 5(7):1469-76. PMID: 17445092. Rudzki Z et al. Mutations in a subgroup of patients with mild haemophilia A and a familial discrepancy between the one-stage and two-stage factor VIII:C methods. Br J Haematol. 1996; 94(2):400-6. PMID: 8759905. Strmecki L et al. Screen of 55 Slovenian haemophilia A patients: identification of 2 novel mutations (S-1R and IVS23+1G-->A) and discussion of mutation spectrum. Hum Mutat. 1999; 13(5):413. PMID: 10338101. - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at