NM_000132.4(F8):c.842C>T (p.Thr281Ile) AND not provided

Germline classification:: Likely pathogenic (1 submission)
Last evaluated:: Jun 26, 2022
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:: RCV003120171.3

Allele description [Variation Report for NM_000132.4(F8):c.842C>T (p.Thr281Ile)]

NM_000132.4(F8):c.842C>T (p.Thr281Ile)

Gene:

F8:coagulation factor VIII [Gene - OMIM - HGNC]

Variant type:

single nucleotide variant

Cytogenetic location:

Xq28

Genomic location:

Preferred name:

NM_000132.4(F8):c.842C>T (p.Thr281Ile)

HGVS:

NC_000023.11:g.154969498G>A
NG_011403.2:g.58226C>T
NM_000132.4:c.842C>TMANE SELECT
NP_000123.1:p.Thr281Ile
LRG_555t1:c.842C>T
LRG_555:g.58226C>T
LRG_555p1:p.Thr281Ile
NC_000023.10:g.154197773G>A

Protein change:

T281I

Molecular consequence:

NM_000132.4:c.842C>T - missense variant - [Sequence Ontology: SO:0001583]

Condition(s)

Synonyms:: none provided
Identifiers:: MedGen: CN517202

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV003799891	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	criteria provided, single submitter (ARUP Molecular Germline Variant Investigation Process 2021)	Likely pathogenic (Jun 26, 2022)	germline	clinical testing	Citation Link

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV003799891

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

criteria provided, single submitter

(ARUP Molecular Germline Variant Investigation Process 2021)

Likely pathogenic
(Jun 26, 2022)

germline

clinical testing

Citation Link

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

Details of each submission

From ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories, SCV003799891.2

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	not provided

Description

The F8 c.842C>T; p.Thr281Ile variant is reported in the literature in multiple individuals affected with mild hemophilia A (see F8 database and references therein). This variant is absent from the Genome Aggregation Database, indicating it is not a common polymorphism. Additionally, other variants at this codon (c.841A>C, p.Thr281Pro; c.842C>A, p.Thr281Asn) have been reported in individuals with mild hemophilia A and are considered disease causing (See F8 database, Markoff 2009). The threonine at codon 281 is highly conserved, and computational analyses predict that this variant is deleterious (REVEL: 0.932). Based on available information, this variant is considered to be likely pathogenic. References: Link to F8 database: https://f8-db.eahad.org/index.php Markoff A et al. Combined homology modelling and evolutionary significance evaluation of missense mutations in blood clotting factor VIII to highlight aspects of structure and function. Haemophilia. 2009 Jul;15(4):932-41. PMID: 19473423.

#	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: Mar 4, 2023

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