NM_000132.4(F8):c.1660A>G (p.Ser554Gly) AND Hereditary factor VIII deficiency disease

Germline classification:: Pathogenic (3 submissions)
Last evaluated:: Feb 2, 2024
Review status:: 3 stars out of maximum of 4 stars
reviewed by expert panel

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:: RCV000010939.21

Allele description [Variation Report for NM_000132.4(F8):c.1660A>G (p.Ser554Gly)]

NM_000132.4(F8):c.1660A>G (p.Ser554Gly)

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.1660A>G (p.Ser554Gly)

Other names:

F8, SER535GLY; S535G; NM_000132.3(F8):c.1660A>G

HGVS:

NC_000023.11:g.154957049T>C
NG_011403.2:g.70675A>G
NM_000132.4:c.1660A>GMANE SELECT
NP_000123.1:p.Ser554Gly
NP_000123.1:p.Ser554Gly
LRG_555t1:c.1660A>G
LRG_555:g.70675A>G
LRG_555p1:p.Ser554Gly
NC_000023.10:g.154185324T>C
NG_011403.1:g.70675A>G
NM_000132.3:c.1660A>G
P00451:p.Ser554Gly

Protein change:

S554G; SER535GLY

Links:

UniProtKB: P00451#VAR_001111; OMIM: 300841.0143; dbSNP: rs137852419

NCBI 1000 Genomes Browser:

rs137852419

Molecular consequence:

NM_000132.4:c.1660A>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

Recent activity

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Uncultured Glomerales isolate soil 6599 5.8S ribosomal RNA gene, partial sequenc...
Uncultured Glomerales isolate soil 6599 5.8S ribosomal RNA gene, partial sequence; internal transcribed spacer 2, complete sequence; and large subunit ribosomal RNA gene, partial sequence
gi|1216365344|gb|MF487785.1|

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV000031166	OMIM	no assertion criteria provided	Pathogenic (Jan 1, 1995)	germline	literature only	PubMed (1) [See all records that cite this PMID]
SCV004038380	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	criteria provided, single submitter (LabCorp Variant Classification Summary - May 2015)	Pathogenic (Aug 8, 2023)	germline	clinical testing	PubMed (2) [See all records that cite these PMIDs] 22103590, 1301932 Citation Link,
SCV004363674	ClinGen Coagulation Factor Deficiency Variant Curation Expert Panel, Clingen	reviewed by expert panel (ClinGen CoagFactor ACMG Specifications F8 V1.0.0)	Pathogenic (Feb 2, 2024)	germline	curation	Citation Link

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV000031166

OMIM

no assertion criteria provided

Pathogenic
(Jan 1, 1995)

germline

literature only

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

SCV004038380

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

criteria provided, single submitter

(LabCorp Variant Classification Summary - May 2015)

Pathogenic
(Aug 8, 2023)

germline

clinical testing

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

Citation Link,

SCV004363674

ClinGen Coagulation Factor Deficiency Variant Curation Expert Panel, Clingen

reviewed by expert panel

(ClinGen CoagFactor ACMG Specifications F8 V1.0.0)

Pathogenic
(Feb 2, 2024)

germline

curation

Citation Link

Help

Summary from all submissions

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

Citations

PubMed

Molecular etiology of factor VIII deficiency in hemophilia A.

Antonarakis SE, Kazazian HH, Tuddenham EG.

Hum Mutat. 1995;5(1):1-22. Review.

PubMed [citation]

PMID:: 7728145

F8 and F9 mutations in US haemophilia patients: correlation with history of inhibitor and race/ethnicity.

Miller CH, Benson J, Ellingsen D, Driggers J, Payne A, Kelly FM, Soucie JM, Craig Hooper W; Hemophilia Inhibitor Research Study Investigators..

Haemophilia. 2012 May;18(3):375-82. doi: 10.1111/j.1365-2516.2011.02700.x. Epub 2011 Nov 21.

PubMed [citation]

PMID:: 22103590

See all PubMed Citations (3)

Details of each submission

From OMIM, SCV000031166.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	literature only	PubMed (1)

Description

Antonarakis et al. (1995) reported this mutation in 2 patients with mild hemophilia A (306700). The mutation is caused by a AGT-to-GGT transition at codon 535 in exon 11 of the A2 domain, resulting in glycine for serine-535.

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

From Women's Health and Genetics/Laboratory Corporation of America, LabCorp, SCV004038380.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (2)

Description

Variant summary: F8 c.1660A>G (p.Ser554Gly) results in a non-conservative amino acid change located in the multicopper oxidase-like, N-terminal domain (IPR011707) of the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 5.5e-06 in 183446 control chromosomes (gnomAD). c.1660A>G (also known as Ser535Gly) has been reported in the literature in multiple individuals affected with mild Factor VIII Deficiency (Hemophilia A) (examples: Diamond_1992 and Miller_2012). 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: 22103590, 1301932). Three submitters have cited clinical-significance assessments for this variant to ClinVar after 2014. All submitters classified the variant as pathogenic/likely pathogenic. 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

From ClinGen Coagulation Factor Deficiency Variant Curation Expert Panel, Clingen, SCV004363674.2

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

Description

The c.1660A>G (p.Ser554Gly) missense variant has a REVEL score of 0.938 which meets PP3 criteria (threshold >0.6). This variant is present in 1 hemizygote in gnomAD v2.1.1 and therefore, does not meet criteria for rarity in the population. Fifty-three patients are reported in Johnsen, et. al. 2107 with mild/moderate hemophilia A and the Gly554Ser variant, meeting F8 phenotype criteria for PS4_Very strong and PP4_Moderate (PMID: 29296726). The variant has been found to segregate with hemophilia A across 6 meioses among 4 different families, the PP1 criteria at the strong weight (Internal VCEP contributor). This variant has been reported in individuals who developed an inhibitor to factor replacement therapy and discrepant chromogenic and one-stage factor VIII activity levels (CDC CHAMPS database/Internal VCEP contributor). In summary, this variant meets criteria to be classified as pathogenic. ACMG/AMP criteria applied, as specified by the Coagulation Factor Deficiency Variant Curation Expert Panel for F8: PS4_Very strong, PP1_Strong, PP4_Moderate, PP3.

#	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: Oct 13, 2024

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