ClinVar Miner

Submissions for variant NM_000132.3(F8):c.2994T>G (p.His998Gln) (rs149853218)

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Total submissions: 2
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Illumina Clinical Services Laboratory,Illumina RCV000356509 SCV000482097 likely benign Hemophilia A, FVIII Deficiency 2016-06-14 criteria provided, single submitter clinical testing
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories RCV000756118 SCV000883837 likely benign not provided 2018-06-27 criteria provided, single submitter clinical testing The c.2994T>G; p.His998Gln variant (rs149853218), also known as His979Gln, has been reported in a patient with severe hemophilia A (Guillet 2006). It is reported as likely benign in ClinVar (Variation ID: 368119) and is observed in the African population at an overall frequency of 1.3% (241/18104 alleles, 2 homozygotes, 73 hemizygotes) in the Genome Aggregation Database. The histidine at residue 998 is moderately conserved, and located in the B-domain, which is removed during F8 maturation and not required for function (Graw 2005). Computational algorithms (PolyPhen-2, SIFT) predict that the variant has no impact on the protein, and it is not located near the thrombin binding or cleavage sites required for B-domain removal (Graw 2005). However, in vitro studies demonstrated reduced relative secretion when expressed in the HEK293T cell line (Pahl 2013). Based on available information, this variant is considered likely benign. References: Graw J et al. Haemophilia A: from mutation analysis to new therapies. Nat Rev Genet. 2005;6(6):488-501. Guillet B et al. Detection of 95 novel mutations in coagulation factor VIII gene F8 responsible for hemophilia A: results from a single institution. Hum Mutat. 2006;27(7):676-85. Pahl S et al. Effect of F8 B domain gene variants on synthesis, secretion, activity and stability of factor VIII protein. Thromb Haemost. 2014;111(1):58-66.

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