ClinVar Miner

Submissions for variant NM_000132.4(F8):c.2162T>C (p.Met721Thr)

dbSNP: rs1314906579
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Total submissions: 1
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories RCV001802530 SCV002048785 pathogenic Hereditary factor VIII deficiency disease 2021-08-24 criteria provided, single submitter clinical testing The F8 c.2162T>C; p.Met721Thr variant (rs1314906579) is reported in the literature in multiple individuals affected with severe hemophilia A (see link to F8 database and references therein). This variant is absent from the Genome Aggregation Database, indicating it is not a common polymorphism. Additionally, other amino acid substitutions at this codon (Met721Leu, Met721Val, Met721Ile) have been reported in individuals with mild to severe hemophilia A and are considered pathogenic (F8 database, Johnsen 2017, Liu 2002, Santacroce 2008). The methionine at codon 721 is moderately conserved, and computational analyses predict that this variant is deleterious (REVEL: 0.946). Based on available information, this variant is considered to be pathogenic. References: Link to F8 database: https://f8-db.eahad.org/index.php Johnsen JM et al. Novel approach to genetic analysis and results in 3000 hemophilia patients enrolled in the My Life, Our Future initiative. Blood Adv. 2017 May 18;1(13):824-834. PMID: 29296726. Liu ML et al. Non-inversion factor VIII mutations in 80 hemophilia A families including 24 with alloimmune responses. Thromb Haemost. 2002 Feb;87(2):273-6. PMID: 11858487. Santacroce R et al. Identification of 217 unreported mutations in the F8 gene in a group of 1,410 unselected Italian patients with hemophilia A. J Hum Genet. 2008;53(3):275-284. PMID: 18217193.

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