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NM_000133.4(F9):c.676C>T (p.Arg226Trp) AND Hereditary factor IX deficiency disease

Germline classification:
Pathogenic/Likely pathogenic (4 submissions)
Last evaluated:
Apr 4, 2024
Review status:
2 stars out of maximum of 4 stars
criteria provided, multiple submitters, no conflicts
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:
RCV000011336.18

Allele description [Variation Report for NM_000133.4(F9):c.676C>T (p.Arg226Trp)]

NM_000133.4(F9):c.676C>T (p.Arg226Trp)

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.676C>T (p.Arg226Trp)
Other names:
F9, ARG180TRP; R180W
HGVS:
  • NC_000023.11:g.139551217C>T
  • NG_007994.1:g.25482C>T
  • NM_000133.4:c.676C>TMANE SELECT
  • NM_001313913.2:c.562C>T
  • NP_000124.1:p.Arg226Trp
  • NP_001300842.1:p.Arg188Trp
  • LRG_556t1:c.676C>T
  • LRG_556:g.25482C>T
  • NC_000023.10:g.138633376C>T
  • NM_000133.3:c.676C>T
  • P00740:p.Arg226Trp
Protein change:
R188W; ARG180TRP
Links:
UniProtKB: P00740#VAR_006570; OMIM: 300746.0030; dbSNP: rs137852240
NCBI 1000 Genomes Browser:
rs137852240
Molecular consequence:
  • NM_000133.4:c.676C>T - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001313913.2:c.562C>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

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Assertion and evidence details

Submission AccessionSubmitterReview Status
(Assertion method)
Clinical Significance
(Last evaluated)
OriginMethodCitations
SCV000031567OMIM
no assertion criteria provided
Pathogenic
(Dec 15, 1989)
germlineliterature only

PubMed (2)
[See all records that cite these PMIDs]

SCV002556711Genetics and Molecular Pathology, SA Pathology

See additional submitters

criteria provided, single submitter

(ACMG Guidelines, 2015)
Likely pathogenic
(Apr 22, 2021)
germlineclinical testing

PubMed (1)
[See all records that cite this PMID]

SCV002765918Women's Health and Genetics/Laboratory Corporation of America, LabCorp
criteria provided, single submitter

(LabCorp Variant Classification Summary - May 2015)
Pathogenic
(Nov 22, 2022)
germlineclinical testing

PubMed (3)
[See all records that cite these PMIDs]

Citation Link,

SCV004809708Center for Genomic Medicine, King Faisal Specialist Hospital and Research Center
criteria provided, single submitter

(ACMG Guidelines, 2015)
Pathogenic
(Apr 4, 2024)
germlineclinical testing

PubMed (1)
[See all records that cite this PMID]

Summary from all submissions

EthnicityOriginAffectedIndividualsFamiliesChromosomes testedNumber TestedFamily historyMethod
not providedgermlineyesnot providednot providednot providednot providednot providedclinical testing
not providedgermlineunknownnot providednot providednot providednot providednot providedclinical testing
not providedgermlinenot providednot providednot providednot providednot providednot providedliterature only

Citations

PubMed

Blood clotting factor IX BM Nagoya. Substitution of arginine 180 by tryptophan and its activation by alpha-chymotrypsin and rat mast cell chymase.

Suehiro K, Kawabata S, Miyata T, Takeya H, Takamatsu J, Ogata K, Kamiya T, Saito H, Niho Y, Iwanaga S.

J Biol Chem. 1989 Dec 15;264(35):21257-65.

PubMed [citation]
PMID:
2592373

The abnormal factor IX of hemophilia B+ variants.

Bertina RM, Veltkamp JJ.

Thromb Haemost. 1978 Oct 31;40(2):335-49.

PubMed [citation]
PMID:
734633
See all PubMed Citations (6)

Details of each submission

From OMIM, SCV000031567.2

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1not providednot providednot providednot providedliterature only PubMed (2)

Description

This variant has been called factor IX B(M) Nagoya and factor IX Deventer.

Suehiro et al. (1989) demonstrated substitution of tryptophan for arginine at position 180 in the factor IX protein of a patient with severe hemophilia B (306900). Bertina et al. (1990) found the same mutation.

#SampleMethodObservation
OriginAffectedNumber testedTissuePurposeMethodIndividualsAllele frequencyFamiliesCo-occurrences
1germlinenot providednot providednot providednot providednot providednot providednot providednot provided

From Genetics and Molecular Pathology, SA Pathology, SCV002556711.2

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1not providednot providednot providednot providedclinical testing PubMed (1)
#SampleMethodObservation
OriginAffectedNumber testedTissuePurposeMethodIndividualsAllele frequencyFamiliesCo-occurrences
1germlineyesnot providednot providednot providednot providednot providednot providednot provided

From Women's Health and Genetics/Laboratory Corporation of America, LabCorp, SCV002765918.1

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1not providednot providednot providednot providedclinical testing PubMed (3)

Description

Variant summary: F9 c.676C>T (p.Arg226Trp) results in a non-conservative amino acid change located in the Serine proteases, 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 183448 control chromosomes (gnomAD). c.676C>T has been reported in the literature in multiple individuals affected with Factor IX Deficiency (Hemophilia B) (examples: Ludwig_1992, Hamasaki-Katagiri_2012, Branchini_2021). These data indicate that the variant is very 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 <10% of normal activity (example: Branchini_2021). Other variants affecting the same amino acid (e.g R226Q, R226G) has been reported in patients with severe form of Hemophila B (Hamasaki-Katagiri_2012, Branchini_2021 and HGMD). Two clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 and classified the variant as pathogenic/likely pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic.

#SampleMethodObservation
OriginAffectedNumber testedTissuePurposeMethodIndividualsAllele frequencyFamiliesCo-occurrences
1germlineunknownnot providednot providednot providednot providednot providednot providednot provided

From Center for Genomic Medicine, King Faisal Specialist Hospital and Research Center, SCV004809708.1

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1not providednot providednot providednot providedclinical testing PubMed (1)
#SampleMethodObservation
OriginAffectedNumber testedTissuePurposeMethodIndividualsAllele frequencyFamiliesCo-occurrences
1germlineunknownnot providednot providednot providednot providednot providednot providednot provided

Last Updated: Oct 26, 2024