NM_000132.4(F8):c.6769A>G (p.Met2257Val) AND Hereditary factor VIII deficiency disease

Germline classification:: Benign (3 submissions)
Last evaluated:: Feb 1, 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:: RCV000033894.28

Allele description [Variation Report for NM_000132.4(F8):c.6769A>G (p.Met2257Val)]

NM_000132.4(F8):c.6769A>G (p.Met2257Val)

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.6769A>G (p.Met2257Val)

Other names:

NM_000132.3(F8):c.6769A>G

HGVS:

NC_000023.11:g.154860563T>C
NG_011403.2:g.167161A>G
NM_000132.4:c.6769A>GMANE SELECT
NM_019863.3:c.364A>G
NP_000123.1:p.Met2257Val
NP_000123.1:p.Met2257Val
NP_000123.1:p.Met2257Val
NP_063916.1:p.Met122Val
NP_063916.1:p.Met122Val
LRG_555t1:c.6769A>G
LRG_555:g.167161A>G
LRG_555p1:p.Met2257Val
NC_000023.10:g.154088838T>C
NG_011403.1:g.167161A>G
NM_000132.3:c.6769A>G
NM_019863.2:c.364A>G
P00451:p.Met2257Val
NM_000132.3:c.6771A>G

Note:

NCBI staff reviewed the information reported in PubMed 17209060 to determine the location of this allele on current reference sequence.

Protein change:

M122V

Links:

UniProtKB: P00451#VAR_021356; dbSNP: rs1800297

NCBI 1000 Genomes Browser:

rs1800297

Molecular consequence:

NM_000132.4:c.6769A>G - missense variant - [Sequence Ontology: SO:0001583]
NM_019863.3:c.364A>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: 306700

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV000057802	GeneReviews	no assertion criteria provided	benign (Sep 22, 2011)	not provided	curation
SCV000482091	Illumina Laboratory Services, Illumina	criteria provided, single submitter (ICSL Variant Classification Criteria 13 December 2019)	Benign (Apr 27, 2017)	germline	clinical testing	PubMed (3) [See all records that cite these PMIDs] 23711237, 20301578, 7579394 Citation Link,
SCV004363673	ClinGen Coagulation Factor Deficiency Variant Curation Expert Panel, Clingen	reviewed by expert panel (ClinGen CoagFactor ACMG Specifications F8 V1.0.0)	Benign (Feb 1, 2024)	germline	curation	Citation Link

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV000057802

GeneReviews

no assertion criteria provided

benign
(Sep 22, 2011)

not provided

curation

SCV000482091

Illumina Laboratory Services, Illumina

criteria provided, single submitter

(ICSL Variant Classification Criteria 13 December 2019)

Benign
(Apr 27, 2017)

germline

clinical testing

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

Citation Link,

SCV004363673

ClinGen Coagulation Factor Deficiency Variant Curation Expert Panel, Clingen

reviewed by expert panel

(ClinGen CoagFactor ACMG Specifications F8 V1.0.0)

Benign
(Feb 1, 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	unknown	not provided	not provided	not provided	not provided	not provided	clinical testing, curation
not provided	not provided	not provided	not provided	not provided	not provided	not provided	not provided	curation

Citations

PubMed

Detection of new mutations and molecular pathology of mild and moderate haemophilia A patients from southern Brazil.

Rosset C, Vieira IA, Sinigaglia M, Gorziza RP, Salzano FM, Bandinelli E.

Haemophilia. 2013 Sep;19(5):773-81. doi: 10.1111/hae.12172. Epub 2013 May 28.

PubMed [citation]

PMID:: 23711237

Hemophilia A..

Konkle BA, Nakaya Fletcher S.

2000 Sep 21 [updated 2023 Jul 27]. In: Adam MP, Feldman J, Mirzaa GM, Pagon RA, Wallace SE, Amemiya A, editors. GeneReviews(®) [Internet]. Seattle (WA): University of Washington, Seattle; 1993-2024.

PubMed [citation]

PMID:: 20301578

See all PubMed Citations (3)

Details of each submission

From GeneReviews, SCV000057802.2

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

Description

Converted during submission to Benign.

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

From Illumina Laboratory Services, Illumina, SCV000482091.3

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (3)

Description

This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). Publications were found based on this search. The evidence from the literature, in combination with allele frequency data from public databases where available, was sufficient to rule this variant out of causing disease. Therefore, this variant is classified as benign.

#	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, SCV004363673.2

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

Description

The missense variant, NM_000132.3(F8):c.6769A>G (p.Met2257Val), is reported at an MAF of 0.2418 (4578/18936 with 1245 hemizygotes) in the African population in gnomAD v2.1.1. A REVEL score of 0.292 and SpliceAI score of 0 meets BP4 cut-off (respective thresholds <0.3 and <0.05). In summary, this variant meets criteria to be classified as benign. ACMG/AMP criteria applied, as specified by the Coagulation Factor Deficiency variant curation expert panel for F8: BA1, BP4.

#	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: Dec 28, 2024

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