NM_000133.4(F9):c.1293G>T (p.Trp431Cys) AND multiple conditions

Germline classification:: Pathogenic (1 submission)
Last evaluated:: Apr 12, 2023
Review status:: 1 star out of maximum of 4 stars
criteria provided, single submitter

Somatic classification of clinical impact:: None
Review status:: (0/4) 0 stars out of maximum of 4 stars
no assertion criteria provided

Somatic classification of oncogenicity:: None
Review status:: (0/4) 0 stars out of maximum of 4 stars
no assertion criteria provided

Record status:: current
Accession:: RCV003783795.2

Allele description [Variation Report for NM_000133.4(F9):c.1293G>T (p.Trp431Cys)]

NM_000133.4(F9):c.1293G>T (p.Trp431Cys)

Gene:

F9:coagulation factor IX [Gene - OMIM - HGNC]

Variant type:

single nucleotide variant

Cytogenetic location:

Xq27.1

Genomic location:

Preferred name:

NM_000133.4(F9):c.1293G>T (p.Trp431Cys)

HGVS:

NC_000023.11:g.139561978G>T
NG_007994.1:g.36243G>T
NM_000133.4:c.1293G>TMANE SELECT
NM_001313913.2:c.1179G>T
NP_000124.1:p.Trp431Cys
NP_000124.1:p.Trp431Cys
NP_001300842.1:p.Trp393Cys
LRG_556t1:c.1293G>T
LRG_556:g.36243G>T
LRG_556p1:p.Trp431Cys
NC_000023.10:g.138644137G>T
NM_000133.3:c.1293G>T

Protein change:

W393C

Molecular consequence:

NM_000133.4:c.1293G>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001313913.2:c.1179G>T - missense variant - [Sequence Ontology: SO:0001583]

Condition(s)

Name:: Hereditary factor IX deficiency disease (HEMB)
Synonyms:: F9 DEFICIENCY; PLASMA THROMBOPLASTIN COMPONENT DEFICIENCY; Hemophilia B; See all synonyms [MedGen]
Identifiers:: MONDO: MONDO:0010604; MeSH: D002836; MedGen: C0008533; Orphanet: 98879; OMIM: 306900

Name:: Thrombophilia, X-linked, due to factor 9 defect
Synonyms:: Thrombophilia, X-linked, due to factor IX defect
Identifiers:: MONDO: MONDO:0010432; MedGen: C2749016; OMIM: 300807

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV004571549	Labcorp Genetics (formerly Invitae), Labcorp	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Pathogenic (Apr 12, 2023)	germline	clinical testing	PubMed (4) [See all records that cite these PMIDs] 22639855, 7937052, 19699296, 28492532

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV004571549

Labcorp Genetics (formerly Invitae), Labcorp

criteria provided, single submitter

(Invitae Variant Classification Sherloc (09022015))

Pathogenic
(Apr 12, 2023)

germline

clinical testing

PubMed (4)
[See all records that cite these PMIDs]

Help

Summary from all submissions

Ethnicity	Origin	Affected	Individuals	Families	Chromosomes tested	Number Tested	Family history	Method
not provided	germline	unknown	not provided	not provided	not provided	not provided	not provided	clinical testing

Citations

PubMed

Analysis of F9 point mutations and their correlation to severity of haemophilia B disease.

Hamasaki-Katagiri N, Salari R, Simhadri VL, Tseng SC, Needlman E, Edwards NC, Sauna ZE, Grigoryan V, Komar AA, Przytycka TM, Kimchi-Sarfaty C.

Haemophilia. 2012 Nov;18(6):933-40. doi: 10.1111/j.1365-2516.2012.02848.x. Epub 2012 May 29.

PubMed [citation]

PMID:: 22639855

Haemophilia B: database of point mutations and short additions and deletions, fifth edition, 1994.

Giannelli F, Green PM, Sommer SS, Lillicrap DP, Ludwig M, Schwaab R, Reitsma PH, Goossens M, Yoshioka A, Brownlee GG.

Nucleic Acids Res. 1994 Sep;22(17):3534-46.

PubMed [citation]

PMID:: 7937052
PMCID:: PMC308314

See all PubMed Citations (4)

Details of each submission

From Labcorp Genetics (formerly Invitae), Labcorp, SCV004571549.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (4)

Description

For these reasons, this variant has been classified as Pathogenic. This variant disrupts the p.Trp431 amino acid residue in F9. Other variant(s) that disrupt this residue have been observed in individuals with F9-related conditions (PMID: 7937052, 19699296, 22639855), which suggests that this may be a clinically significant amino acid residue. 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. This variant is also known as 31.276G>T 385W>C. This missense change has been observed in individuals with hemophilia B (PMID: 7937052, 19699296; Invitae). This variant is not present in population databases (gnomAD no frequency). This sequence change replaces tryptophan, which is neutral and slightly polar, with cysteine, which is neutral and slightly polar, at codon 431 of the F9 protein (p.Trp431Cys).

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	unknown	not provided	not provided	not provided		not provided	not provided	not provided	not provided

Last Updated: Sep 29, 2024

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