Submissions for variant NM_000132.4(F8):c.1018G>A (p.Glu340Lys)

gnomAD frequency: 0.00019  dbSNP: rs781954986

Total submissions: 6

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Mayo Clinic Laboratories, Mayo Clinic	RCV001508074	SCV001713981	uncertain significance	not provided	2020-04-14	criteria provided, single submitter	clinical testing
Mendelics	RCV002246393	SCV002519680	pathogenic	Thrombophilia, X-linked, due to factor 8 defect	2022-05-04	criteria provided, single submitter	clinical testing
Genetics and Molecular Pathology, SA Pathology	RCV002272475	SCV002557022	uncertain significance	Hereditary factor VIII deficiency disease	2020-12-29	criteria provided, single submitter	clinical testing
Revvity Omics, Revvity	RCV001508074	SCV004234739	uncertain significance	not provided	2022-07-18	criteria provided, single submitter	clinical testing
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	RCV001508074	SCV004562238	pathogenic	not provided	2023-06-20	criteria provided, single submitter	clinical testing	The F8 c.1018G>A; p.Glu340Lys variant (rs781954986), also known as E321K, is reported in the literature in multiple individuals affected with mild hemophilia A (Jayandharan 2005, Markoff 2009, Prabhudesai 2017, Waseem 1999). This variant is found in the South Asian population with an allele frequency of 0.18% (34/19075 alleles) in the Genome Aggregation Database. Computational analyses predict that this variant is deleterious (REVEL: 0.758). Additionally, another variant at this codon (c.1020A>C; p.Glu240Asp) has been reported in individuals with mild hemophilia A (Green 2008). Based on available information, this variant is considered to be pathogenic. References: Green PM et al. Haemophilia A mutations in the UK: results of screening one-third of the population. Br J Haematol. 2008 Oct;143(1):115-28. PMID: 18691168. Jayandharan G et al. Identification of factor VIII gene mutations in 101 patients with haemophilia A: mutation analysis by inversion screening and multiplex PCR and CSGE and molecular modelling of 10 novel missense substitutions. Haemophilia. 2005 Sep;11(5):481-91. PMID: 16128892. 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 Jul;15(4):932-41. PMID: 19473423. Prabhudesai A et al. A de novo factor VIII mutation in a haemophilia B family leading to combined deficiency of factor VIII and IX. Haemophilia. 2017 Sep;23(5):e477-e479. PMID: 28750473 Waseem NH et al. Start of UK confidential haemophilia A database: analysis of 142 patients by solid phase fluorescent chemical cleavage of mismatch. Haemophilia Centres. Thromb Haemost. 1999 Jun;81(6):900-5. PMID: 10404764.
PreventionGenetics, part of Exact Sciences	RCV004746413	SCV005359221	uncertain significance	F8-related disorder	2024-06-14	no assertion criteria provided	clinical testing	The F8 c.1018G>A variant is predicted to result in the amino acid substitution p.Glu340Lys. This variant has been reported in multiple individuals with mild hemophilia A (Table 2, Waseem et al. 1999. PubMed ID: 10404764; Table S1, Markoff et al. 2009. PubMed ID: 19473423). This variant has also been reported to co-segregate in a family with hemophilia B; however, all the affected individuals also harbored a pathogenic missense variant in F9 (Figure 1, Prabhudesai et al. 2017. PubMed ID: 28750473). This variant is reported in 0.18% of alleles in individuals of South Asian descent including 18 hemizygotes in gnomAD. This variant has classifications ranging from pathogenic to uncertain by other institutions in ClinVar (https://www.ncbi.nlm.nih.gov/clinvar/variation/1163210/). At this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence.