Submissions for variant NM_000133.4(F9):c.1025C>T (p.Thr342Met)

dbSNP: rs137852254

Total submissions: 12

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
ClinGen Coagulation Factor Deficiency Variant Curation Expert Panel, Clingen	RCV000011353	SCV004363682	pathogenic	Hereditary factor IX deficiency disease	2024-02-09	reviewed by expert panel	curation	The c.1025C>T; p.Thr342Met variant is completely absent from gnomAD v2.1.1 and v3.1.1. This missense variant has a REVEL score of 0.799 and meets PP3 criteria (threshold >0.6). There are over 100 patients are reported in the literature with mild to severe hemophilia B and this variant, meeting F9 phenotype criteria for PP4_Moderate and PS4_Very strong (PMID: 29296726, 8314564). In summary, this variant meets criteria to be classified as pathogenic. ACMG/AMP criteria applied, as specified by the Coagulation Factor Deficiency Variant Curation Expert Panel for F9: PS4_Very strong, PP4_Moderate, PP3, PM2_Supporting.
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	RCV001810849	SCV000603536	pathogenic	not provided	2021-08-17	criteria provided, single submitter	clinical testing	The F9 c.1025C>T; p.Thr342Met variant (rs137852254), also known as Thr296Met, has been described in the literature in individuals with variable hemophilia B severity (see link to F9 database and references therein, Bicocchi 2006, Ketterline 1991, Radic 2013, Sharathkumar 2009). The variant is listed is also reported in ClinVar (Variation ID: 10607), and is absent from general population databases (Exome Variant Server, and Genome Aggregation Database), indicating it is not a common polymorphism. The threonine at codon 342 is highly conserved, and computational analyses predict that this variant is deleterious (REVEL: 0.799). Additionally, other variants at this codon (c.1024A>G; p.Thr342Ala, c.1024A>C; p.Thr342Arg, c.1025C>A; p.Thr342Lys) have been described in individuals affected with hemophilia B and are considered pathogenic (see link to F9 database and references therein). Based on available information, the p.Thr342Met variant is considered pathogenic for hemophilia B with variable outcomes. REFERENCES Link to F9 database: http://www.factorix.org/ Bicocchi MP et al. Insight into molecular changes of the FIX protein in a series of Italian patients with haemophilia B. Haemophilia. 2006 12(3):263-70. Ketterling RP et al. T296----M, a common mutation causing mild hemophilia B in the Amish and others: founder effect, variability in factor IX activity assays, and rapid carrier detection. Hum Genet. 1991 87(3):333-7. Radic CP et al. Assessment of the F9 genotype-specific FIX inhibitor risks and characterisation of 10 novel severe F9 defects in the first molecular series of Argentinian patients with haemophilia B. Thromb Haemost. 2013 109(1):24-33. Sharathkumar A et al. Variability in bleeding phenotype in Amish carriers of haemophilia B with the 31008 C-->T mutation. Haemophilia. 2009 15(1):91-100.
NIHR Bioresource Rare Diseases, University of Cambridge	RCV000851963	SCV000899402	likely pathogenic	Hereditary factor VIII deficiency disease	2019-02-01	criteria provided, single submitter	research
Labcorp Genetics (formerly Invitae), Labcorp	RCV000792734	SCV000932048	pathogenic	Hereditary factor IX deficiency disease; Thrombophilia, X-linked, due to factor 9 defect	2024-01-13	criteria provided, single submitter	clinical testing	This sequence change replaces threonine, which is neutral and polar, with methionine, which is neutral and non-polar, at codon 342 of the F9 protein (p.Thr342Met). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individuals with hemophilia B (PMID: 1864609, 2066105, 22639855). It is commonly reported in individuals of Amish ancestry (PMID: 1864609, 2066105, 22639855). This variant is also known as Thr296Met. ClinVar contains an entry for this variant (Variation ID: 10607). 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) performed at Invitae indicates that this missense variant is expected to disrupt F9 protein function with a positive predictive value of 95%. For these reasons, this variant has been classified as Pathogenic.
Mayo Clinic Laboratories, Mayo Clinic	RCV001810849	SCV002573772	pathogenic	not provided	2021-09-02	criteria provided, single submitter	clinical testing	PP5, PM2, PM5, PS4_moderate
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000011353	SCV004037939	pathogenic	Hereditary factor IX deficiency disease	2023-08-17	criteria provided, single submitter	clinical testing	Variant summary: F9 c.1025C>T (p.Thr342Met) results in a non-conservative amino acid change located in the trypsin domain (IPR001254) of the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant was absent in 183381 control chromosomes (gnomAD). c.1025C>T has been reported in the literature in numerous individuals affected with Factor IX Deficiency (Hemophilia B) (e.g., Ketterling_1991, Miller_2012, Hamasaki-Katagiri_2012). These data indicate that the variant is very likely to be associated with disease. The following publications have been ascertained in the context of this evaluation (PMID: 22639855, 1864609, 22103590). Five submitters have reported clinical-significance assessments for this variant to ClinVar after 2014. All submitters classified the variant as pathogenic/likely pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic.
Center for Genomic Medicine, King Faisal Specialist Hospital and Research Center	RCV000011353	SCV004809514	pathogenic	Hereditary factor IX deficiency disease	2024-04-04	criteria provided, single submitter	clinical testing
Neuberg Centre For Genomic Medicine, NCGM	RCV000011353	SCV005060881	pathogenic	Hereditary factor IX deficiency disease		criteria provided, single submitter	clinical testing	The observed missense variant c.1025C>T(p.Thr342Met) in F9 gene has been reported previously in multiple individuals with Hemophilia B (Li T, et al., 2014). The other variants at this codon (c.1024A>G; p.Thr342Ala, c.1024A>C; p.Thr342Arg, c.1025C>A; p.Thr342Lys) have been described in individuals affected with hemophilia B and are considered pathogenic (Turro E, et al., 2020). The c.1025C>T variant is absent in gnomAD Exomes. This variant has been reported to the ClinVar database as Likely Pathogenic/ Pathogenic (multiple submissions). The amino acid Threonine at position 342 is changed to a Methionine changing protein sequence and it might alter its composition and physico-chemical properties. The amino acid change p.Thr342Met in F9 is predicted as conserved by GERP++ and PhyloP across 100 vertebrates. For these reasons, this variant has been classified as Pathogenic.
OMIM	RCV000011353	SCV000031585	pathogenic	Hereditary factor IX deficiency disease	1991-07-01	no assertion criteria provided	literature only
NIHR Bioresource Rare Diseases, University of Cambridge	RCV000011353	SCV001161885	pathogenic	Hereditary factor IX deficiency disease		no assertion criteria provided	research
Natera, Inc.	RCV000011353	SCV002082229	pathogenic	Hereditary factor IX deficiency disease	2020-11-25	no assertion criteria provided	clinical testing
PreventionGenetics, part of Exact Sciences	RCV004752696	SCV005351696	pathogenic	F9-related disorder	2024-08-26	no assertion criteria provided	clinical testing	The F9 c.1025C>T variant is predicted to result in the amino acid substitution p.Thr342Met. This variant, also referred to as p.Thr296Met using legacy nomenclature, has been reported in many individuals with mild to severe forms of hemophilia B (Green et al. 1990. PubMed ID: 1972560; see ID number 98 in Belvini et al. 2005. PubMed ID: 15921378; Factor IX Gene (F9) Variant Database: http://www.factorix.org/). This variant has not been reported in a large population database, indicating this variant is rare. This variant is interpreted as pathogenic.