Total submissions: 3
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| Center For Human Genetics And Laboratory Diagnostics, |
RCV001801319 | SCV002047528 | likely pathogenic | Hereditary factor VIII deficiency disease | 2021-10-08 | criteria provided, single submitter | clinical testing | |
| ARUP Laboratories, |
RCV003120694 | SCV003799323 | pathogenic | not provided | 2022-03-24 | criteria provided, single submitter | clinical testing | The F8 c.6443A>G; p.Asn2148Ser variant (rs1321311878), also known as Asn2129Ser, is reported in several individuals with mild to moderate hemophilia A (Factor VIII (F8) Variant Database, Johnsen 2017, Lannoy 2012, Tavassoli 1998). Additionally, other variants at this codon (c.6442A>G, p. Asn2148Asp; c.6444T>A, p.Asn2148Lys) have been reported in individuals with hemophilia A (Feng 2021, Xue 2010). The p.Asn2148Ser variant is absent from the Genome Aggregation Database, indicating it is not a common polymorphism. The asparagine at codon 2148 is highly conserved, and computational analyses predict that this variant is deleterious (REVEL: 0.927). Based on available information, this variant is considered to be pathogenic. References: Factor VIII Gene (F8) Variant Database: https://f8-db.eahad.org/advance_search_results.php Feng Y et al. Mutation analysis in the F8 gene in 485 families with haemophilia A and prenatal diagnosis in China. Haemophilia. 2021 Jan;27(1):e88-e92. PMID: 33245802. 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. Lannoy N et al. Computational and molecular approaches for predicting unreported causal missense mutations in Belgian patients with haemophilia A. Haemophilia. 2012 May;18(3):e331-9. PMID: 21883705. Tavassoli K et al. Molecular diagnostics of 15 hemophilia A patients: characterization of eight novel mutations in the factor VIII gene, two of which result in exon skipping. Hum Mutat. 1998;12(5):301-3. PMID: 9792405. Xue F et al. Factor VIII gene mutations profile in 148 Chinese hemophilia A subjects. Eur J Haematol. 2010 Sep;85(3):264-72. PMID: 20528906. |
| Women's Health and Genetics/Laboratory Corporation of America, |
RCV001801319 | SCV003928798 | likely pathogenic | Hereditary factor VIII deficiency disease | 2023-04-26 | criteria provided, single submitter | clinical testing | Variant summary: F8 c.6443A>G (p.Asn2148Ser) results in a conservative amino acid change located in the Coagulation factor 5/8 C-terminal domain (IPR000421) of the encoded protein sequence. Four of five in-silico tools predict a damaging effect of the variant on protein function. The variant was absent in 183328 control chromosomes. c.6443A>G has been reported in the literature in individuals affected with mild Factor VIII Deficiency (Hemophilia A) (example, Tavassoli_1998, Nance_2013, Eckhardt_2013). These data indicate that the variant is likely to be associated with disease. At least one publication reports experimental evidence evaluating an impact on protein function. The most pronounced variant effect results in reduced binding of Factor VIII to von Wildebrand factor (vWf) at approximately 50% of normal activity (Jacquemin_2000). The following publications have been ascertained in the context of this evaluation (PMID: 11748850, 23926300, 10910910, 23711294, 9792405). Two clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All laboratories classified the variant as pathogenic/likely pathogenic. Based on the evidence outlined above, the variant was classified as likely pathogenic. |