ClinVar Miner

Submissions for variant NM_000133.4(F9):c.881G>A (p.Arg294Gln)

dbSNP: rs137852249
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Total submissions: 10
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
NIHR Bioresource Rare Diseases, University of Cambridge RCV000851909 SCV000899974 pathogenic Hereditary factor VIII deficiency disease 2019-02-01 criteria provided, single submitter research
Labcorp Genetics (formerly Invitae), Labcorp RCV000814168 SCV000954569 pathogenic Hereditary factor IX deficiency disease; Thrombophilia, X-linked, due to factor 9 defect 2023-09-17 criteria provided, single submitter clinical testing This sequence change replaces arginine, which is basic and polar, with glutamine, which is neutral and polar, at codon 294 of the F9 protein (p.Arg294Gln). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individuals with hemophilia B (PMID: 2472424, 19699296, 22544209, 32155688; Invitae). This variant is also known as p.Arg248Gln. ClinVar contains an entry for this variant (Variation ID: 10602). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) has been performed at Invitae for this missense variant, however the output from this modeling did not meet the statistical confidence thresholds required to predict the impact of this variant on F9 protein function. Experimental studies have shown that this missense change affects F9 function (PMID: 29993188). For these reasons, this variant has been classified as Pathogenic.
Neuberg Centre For Genomic Medicine, NCGM RCV000011348 SCV002073155 pathogenic Hereditary factor IX deficiency disease criteria provided, single submitter clinical testing The missense variant p.R294Q in F9 (NM_000133.4 has been reported previously in affected patients with hemophilia B (Chavali et al, 2009; Yu et al, 2012). The p.R294Q variant is novel (not in any individuals) in gnomAD Exomes and is novel (not in any individuals) in 1000 Genomes. Experimental studies have shown that this missense change impairs intracellular trafficking of factor IX (Pignani et al, 2018). It has been submitted to ClinVar as Pathogenic. For these reasons, this variant has been classified as Pathogenic
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV000011348 SCV003922517 pathogenic Hereditary factor IX deficiency disease 2023-03-15 criteria provided, single submitter clinical testing Variant summary: F9 c.881G>A (p.Arg294Gln) results in a conservative amino acid change located in the Serine proteases, trypsin domain (IPR001254) of the encoded protein sequence. Three of five in-silico tools predict a damaging effect of the variant on protein function. The variant was absent in 179083 control chromosomes (gnomAD). c.881G>A has been reported in the literature in multiple individuals affected with Factor IX Deficiency (Hemophilia B) (Chen_1989, Chavali_2009, Onay_2003), including de novo occurrences. These data indicate that the variant is very likely to be associated with disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Four ClinVar submitters (evaluation after 2014) cite this variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic.
3billion RCV000011348 SCV004013531 pathogenic Hereditary factor IX deficiency disease criteria provided, single submitter clinical testing The variant is not observed in the gnomAD v2.1.1 dataset. The variant is located in a mutational hot spot and/or well-established functional domain in which established pathogenic variants have been reported. Missense changes are a common disease-causing mechanism. In silico tool predictions suggest damaging effect of the variant on gene or gene product (REVEL: 0.58; 3Cnet: 0.73). Same nucleotide change resulting in same amino acid change has been previously reported as pathogenic/likely pathogenic with strong evidence (ClinVar ID: VCV000010602 / PMID: 2472424). A different missense change at the same codon (p.Arg294Gly) has been reported to be associated with F9 related disorder (PMID: 7937052). Therefore, this variant is classified as Pathogenic according to the recommendation of ACMG/AMP guideline.
Division of Human Genetics, National Health Laboratory Service/University of the Witwatersrand RCV000011348 SCV004123083 pathogenic Hereditary factor IX deficiency disease 2023-07-01 criteria provided, single submitter research
GeneDx RCV004724733 SCV005332589 pathogenic not provided 2024-03-27 criteria provided, single submitter clinical testing Published functional studies demonstrate a damaging effect (PMID: 29993188); Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant does not alter protein structure/function; This variant is associated with the following publications: (PMID: 31064749, 22639855, 1346975, 32155688, 32224444, 22544209, 19699296, 2472424, 12588353, 29993188)
OMIM RCV000011348 SCV000031580 pathogenic Hereditary factor IX deficiency disease 1992-03-01 no assertion criteria provided literature only
Angelo Bianchi Bonomi Hemophilia and Thrombosis Center, Fondazione IRCCS Ca Granda Ospedale Maggiore Policlinico RCV000011348 SCV001424892 pathogenic Hereditary factor IX deficiency disease 2019-06-01 no assertion criteria provided clinical testing
Natera, Inc. RCV000011348 SCV002083708 pathogenic Hereditary factor IX deficiency disease 2021-08-01 no assertion criteria provided clinical testing

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