NM_000132.4(F8):c.1658C>G (p.Ser553Cys) AND Hereditary factor VIII deficiency disease

Germline classification:: Pathogenic (1 submission)
Last evaluated:: Jan 31, 2024
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:: RCV003988311.1

Allele description [Variation Report for NM_000132.4(F8):c.1658C>G (p.Ser553Cys)]

NM_000132.4(F8):c.1658C>G (p.Ser553Cys)

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.1658C>G (p.Ser553Cys)

HGVS:

NC_000023.11:g.154957051G>C
NG_011403.2:g.70673C>G
NM_000132.4:c.1658C>GMANE SELECT
NP_000123.1:p.Ser553Cys
LRG_555t1:c.1658C>G
LRG_555:g.70673C>G
LRG_555p1:p.Ser553Cys
NC_000023.10:g.154185326G>C

Protein change:

S553C

Molecular consequence:

NM_000132.4:c.1658C>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
SCV004804026	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	criteria provided, single submitter (LabCorp Variant Classification Summary - May 2015)	Pathogenic (Jan 31, 2024)	germline	clinical testing	PubMed (4) [See all records that cite these PMIDs] 23926300, 18691168, 23913812, 21592259 Citation Link

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV004804026

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

criteria provided, single submitter

(LabCorp Variant Classification Summary - May 2015)

Pathogenic
(Jan 31, 2024)

germline

clinical testing

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

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

Citations

PubMed

Factor VIII gene (F8) mutation and risk of inhibitor development in nonsevere hemophilia A.

Eckhardt CL, van Velzen AS, Peters M, Astermark J, Brons PP, Castaman G, Cnossen MH, Dors N, Escuriola-Ettingshausen C, Hamulyak K, Hart DP, Hay CR, Haya S, van Heerde WL, Hermans C, Holmström M, Jimenez-Yuste V, Keenan RD, Klamroth R, Laros-van Gorkom BA, Leebeek FW, Liesner R, et al.

Blood. 2013 Sep 12;122(11):1954-62. doi: 10.1182/blood-2013-02-483263. Epub 2013 Aug 7. Erratum in: Blood. 2014 May 8;123(19):3056.

PubMed [citation]

PMID:: 23926300

Haemophilia A mutations in the UK: results of screening one-third of the population.

Green PM, Bagnall RD, Waseem NH, Giannelli F.

Br J Haematol. 2008 Oct;143(1):115-28. doi: 10.1111/j.1365-2141.2008.07310.x. Epub 2008 Aug 7.

PubMed [citation]

PMID:: 18691168

See all PubMed Citations (4)

Details of each submission

From Women's Health and Genetics/Laboratory Corporation of America, LabCorp, SCV004804026.1

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

Description

Variant summary: F8 c.1658C>G (p.Ser553Cys) results in a non-conservative amino acid change located in the Multicopper oxidase-like, N-terminal domain (IPR011707) of the encoded protein sequence. Three of five in-silico tools predict a damaging effect of the variant on protein function. The variant was absent in 183446 control chromosomes (gnomAD). c.1658C>G has been reported in the literature in multiple individuals affected with Factor VIII Deficiency (Hemophilia A; Green_2008, Seary_2012, Eckhardt_2013, Rydz_2013). 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: 18691168, 23926300, 23913812, 21592259). No submitters have cited clinical-significance assessments for this variant to ClinVar. Based on the evidence outlined above, the variant was classified as pathogenic.

#	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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