NM_000132.4(F8):c.377A>G (p.Lys126Arg) AND Hereditary factor VIII deficiency disease

Germline classification:: Likely pathogenic (1 submission)
Last evaluated:: Aug 22, 2018
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:: RCV001000773.8

Allele description [Variation Report for NM_000132.4(F8):c.377A>G (p.Lys126Arg)]

NM_000132.4(F8):c.377A>G (p.Lys126Arg)

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.377A>G (p.Lys126Arg)

HGVS:

NC_000023.11:g.154996984T>C
NG_011403.2:g.30740A>G
NM_000132.4:c.377A>GMANE SELECT
NP_000123.1:p.Lys126Arg
LRG_555t1:c.377A>G
LRG_555:g.30740A>G
LRG_555p1:p.Lys126Arg
NC_000023.10:g.154225259T>C
NG_011403.1:g.30740A>G

Protein change:

K126R

Links:

dbSNP: rs1603436639

NCBI 1000 Genomes Browser:

rs1603436639

Molecular consequence:

NM_000132.4:c.377A>G - missense variant - [Sequence Ontology: SO:0001583]

Condition(s)

Name:: Hereditary factor VIII deficiency disease (HEMA)
Synonyms:: AUTOSOMAL HEMOPHILIA A; Hemophilia A; Hemophilia A, congenital; See all synonyms [MedGen]
Identifiers:: MONDO: MONDO:0010602; MedGen: C0019069; Orphanet: 98878; OMIM: 134500; OMIM: 306700

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV001157826	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	criteria provided, single submitter (ARUP Molecular Germline Variant Investigation Process)	Likely pathogenic (Aug 22, 2018)	germline	clinical testing	Citation Link

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV001157826

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

criteria provided, single submitter

(ARUP Molecular Germline Variant Investigation Process)

Likely pathogenic
(Aug 22, 2018)

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, SCV001157826.1

#	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.377A>G; p.Lys126Arg variant, also known as K107R in the traditional nomenclature, is reported in the literature in at least one individual affected with hemophilia A (Rydz 2013). This variant is absent from general population databases (1000 Genomes Project, Exome Variant Server, and Genome Aggregation Database), indicating it is not a common polymorphism. Additionally, another variant at this codon (c.377A>C; p.Lys126Thr) has been reported in individuals with severe hemophilia A (Markoff 2009, see link to Factor VIII database). The lysine at codon 126 is highly conserved, and computational analyses (SIFT, PolyPhen-2) predict that this variant is deleterious. Based on available information, the p.Lys126Arg variant is considered to be likely pathogenic. References: Link to Factor VIII database: http://www.factorviii-db.org/ 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. Rydz N et al. The Canadian National Program for hemophilia mutation testing" database: a ten-year review. Am J Hematol. 2013 Dec;88(12):1030-4."

#	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: Jun 17, 2024

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