VCV000041001.28 - ClinVar

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

Germline

Top reviewed classifications are shown here.

Submission summary:

9 submissions

9 submitters

4 conditions

Reviewed by expert panel

Benign

Feb 2024 by ClinGen Coagul… FDA Recognized Database

for Hereditary factor VIII deficiency disease

Somatic

No data submitted for somatic clinical impact

Somatic

No data submitted for oncogenicity

Variant Details

Identifiers

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

Variation ID: 41001 Accession: VCV000041001.28

Type and length

single nucleotide variant, 1 bp

Location

Cytogenetic: Xq28 X: 154860563 (GRCh38) [ NCBI UCSC ] X: 154088838 (GRCh37) [ NCBI UCSC ]

Timeline in ClinVar

	First in ClinVar Help The date this variant first appeared in ClinVar with each type of classification.	Last submission Help The date of the most recent submission for each type of classification for this variant.	Last evaluated Help The most recent date that a submitter evaluated this variant for each type of classification.
Germline	May 3, 2013	Sep 29, 2024	Feb 1, 2024

HGVS

Nucleotide	Protein	Molecular consequence
NM_000132.4:c.6769A>G MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.	NP_000123.1:p.Met2257Val	missense
NM_019863.3:c.364A>G	NP_063916.1:p.Met122Val	missense
NC_000023.11:g.154860563T>C
NC_000023.10:g.154088838T>C
NG_011403.2:g.167161A>G
LRG_555:g.167161A>G
LRG_555t1:c.6769A>G	LRG_555p1:p.Met2257Val
	P00451:p.Met2257Val

... more HGVS ... less HGVS

Protein change

M2257V, M122V

Other names

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

Canonical SPDI

NC_000023.11:154860562:T:C

Functional consequence Help The effect of the variant on RNA or protein function, based on experimental evidence from submitters.

Global minor allele frequency (GMAF) Help The global minor allele frequency calculated by the 1000 Genomes Project. The minor allele at this location is indicated in parentheses and may be different from the allele represented by this VCV record.

0.07788 (C)

Allele frequency Help The frequency of the allele represented by this VCV record.

The Genome Aggregation Database (gnomAD), exomes 0.01951

Exome Aggregation Consortium (ExAC) 0.02512

The Genome Aggregation Database (gnomAD) 0.07378

Trans-Omics for Precision Medicine (TOPMed) 0.07775

1000 Genomes Project 0.07788

1000 Genomes Project 30x 0.08117

NHLBI Exome Sequencing Project (ESP) Exome Variant Server 0.08596

Links

ClinGen: CA343869 UniProtKB: P00451#VAR_021356 dbSNP: rs1800297 VarSome

Comment on variant

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

Genes

Gene	OMIM	ClinGen Gene Dosage Sensitivity Curation		Variation Viewer Help Links to Variation Viewer, a genome browser to view variation data from NCBI databases.	Related variants
Gene	OMIM	HI score Help The haploinsufficiency score for the gene, curated by ClinGen’s Dosage Sensitivity Curation task team.	TS score Help The triplosensitivity score for the gene, curated by ClinGen’s Dosage Sensitivity Curation task team.		Within gene Help The number of variants in ClinVar that are contained within this gene, with a link to view the list of variants.	All Help The number of variants in ClinVar for this gene, including smaller variants within the gene and larger CNVs that overlap or fully contain the gene.
F8		Sufficient evidence for dosage pathogenicity	No evidence available	GRCh38 GRCh37	995	1271

Conditions - Germline

Condition Help The condition for this variant-condition (RCV) record in ClinVar.	Classification Help The aggregate germline classification for this variant-condition (RCV) record in ClinVar. The number of submissions that contribute to this aggregate classification is shown in parentheses. (# of submissions)	Review status Help The aggregate review status for this variant-condition (RCV) record in ClinVar. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the review status.	Last evaluated Help The most recent date that a submitter evaluated this variant for the condition.	Variation/condition record Help The RCV accession number, with most recent version number, for the variant-condition record, with a link to the RCV web page.
Hereditary factor VIII deficiency disease	Benign (3)	reviewed by expert panel	Feb 1, 2024	RCV000033894.28
not specified	Benign (3)	criteria provided, multiple submitters, no conflicts	Jul 31, 2024	RCV000249262.17
Hereditary factor VIII deficiency disease Thrombophilia, X-linked, due to factor 8 defect	Benign (1)	criteria provided, single submitter	May 19, 2022	RCV002490452.8
not provided	Benign (2)	criteria provided, multiple submitters, no conflicts	Nov 28, 2023	RCV003103720.12

Submissions - Germline

Classification Help The submitted germline classification for each SCV record. (Last evaluated)	Review status Help Stars represent the review status, or the level of review supporting the submitted (SCV) record. This value is calculated by NCBI based on data from the submitter. Read our rules for calculating the review status. This column also includes a link to the submitter’s assertion criteria if provided, and the collection method. (Assertion criteria)	Condition Help The condition for the classification, provided by the submitter for this submitted (SCV) record. This column also includes the affected status and allele origin of individuals observed with this variant.	Submitter Help The submitting organization for this submitted (SCV) record. This column also includes the SCV accession and version number, the date this SCV first appeared in ClinVar, and the date that this SCV was last updated in ClinVar.	More information Help This column includes more information supporting the classification, including citations, the comment on classification, and detailed evidence provided as observations of the variant by the submitter.
Benign (Feb 01, 2024)	reviewed by expert panel (ClinGen CoagFactor ACMG Specifications F8 V1.0.0) Method: curation	Hereditary factor VIII deficiency disease (X-linked inheritance) Affected status: unknown Allele origin: germline	ClinGen Coagulation Factor Deficiency Variant Curation Expert Panel, Clingen FDA Recognized Database Accession: SCV004363673.2 First in ClinVar: Feb 14, 2024 Last updated: Jun 23, 2024	Other databases https://erepo.clinicalgenome.org… https://erepo.clinicalgenome.org/evrepo/ui/interpretation/a3bad0b0-ae42-494c-80b7-726b05fbbd9e Comment: 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 … (more) 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. (less)
Benign (-)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	NOT SPECIFIED Affected status: unknown Allele origin: germline	PreventionGenetics, part of Exact Sciences Accession: SCV000302446.1 First in ClinVar: Oct 02, 2016 Last updated: Oct 02, 2016
Benign (Nov 28, 2023)	criteria provided, single submitter (ARUP Molecular Germline Variant Investigation Process 2024) Method: clinical testing	not provided Affected status: unknown Allele origin: germline	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories Accession: SCV000883822.9 First in ClinVar: Feb 18, 2019 Last updated: Feb 20, 2024
Benign (Mar 28, 2016)	criteria provided, single submitter (LMM Criteria) Method: clinical testing	not specified Affected status: unknown Allele origin: germline	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine Accession: SCV000539128.1 First in ClinVar: Oct 02, 2016 Last updated: Oct 02, 2016	Comment: Variant identified in a genome or exome case(s) and assessed due to predicted null impact of the variant or pathogenic assertions in the literature or … (more) Variant identified in a genome or exome case(s) and assessed due to predicted null impact of the variant or pathogenic assertions in the literature or databases. Disclaimer: This variant has not undergone full assessment. The following are preliminary notes: Frequency in ESP (all): 908/10563=8.59% (less) Method: Genome/Exome Filtration
Benign (Apr 27, 2017)	criteria provided, single submitter (ICSL Variant Classification Criteria 13 December 2019) Method: clinical testing	Hereditary factor VIII deficiency disease Affected status: unknown Allele origin: germline	Illumina Laboratory Services, Illumina Accession: SCV000482091.3 First in ClinVar: Dec 06, 2016 Last updated: May 31, 2020	Publications: PubMed (3) PubMed: 23711237‚ 20301578‚ 7579394 Comment: 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, … (more) 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. (less)
Benign (May 19, 2022)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Thrombophilia, X-linked, due to factor 8 defect Hereditary factor VIII deficiency disease Affected status: unknown Allele origin: unknown	Fulgent Genetics, Fulgent Genetics Accession: SCV002802134.1 First in ClinVar: Dec 31, 2022 Last updated: Dec 31, 2022
Benign (Jul 31, 2024)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	not specified Affected status: unknown Allele origin: germline	Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital Accession: SCV005089786.1 First in ClinVar: Aug 04, 2024 Last updated: Aug 04, 2024
Benign (-)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: not provided	not provided (X-linked inheritance) Affected status: yes Allele origin: germline	Breakthrough Genomics, Breakthrough Genomics Accession: SCV005276557.1 First in ClinVar: Sep 29, 2024 Last updated: Sep 29, 2024
benign (Sep 22, 2011)	no assertion criteria provided Method: curation	Hemophilia A Affected status: not provided Allele origin: not provided	GeneReviews Accession: SCV000057802.2 First in ClinVar: Apr 04, 2013 Last updated: May 03, 2013	Comment: Converted during submission to Benign.

Comment:

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.

Comment:

Variant identified in a genome or exome case(s) and assessed due to predicted null impact of the variant or pathogenic assertions in the literature or databases. Disclaimer: This variant has not undergone full assessment. The following are preliminary notes: Frequency in ESP (all): 908/10563=8.59%

Comment:

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.

Germline Functional Evidence

There is no functional evidence in ClinVar for this variation. If you have generated functional data for this variation, please consider submitting that data to ClinVar.

Comment:

Citations for germline classification of this variant

Title	Author	Journal	Year	Link
Hemophilia A.	Adam MP	-	2023	PMID: 20301578
Detection of new mutations and molecular pathology of mild and moderate haemophilia A patients from southern Brazil.	Rosset C	Haemophilia : the official journal of the World Federation of Hemophilia	2013	PMID: 23711237
A sequence variation scan of the coagulation factor VIII (FVIII) structural gene and associations with plasma FVIII activity levels.	Viel KR	Blood	2007	PMID: 17209060
Eleven novel mutations in the factor VIII gene from Brazilian hemophilia A patients.	Arruda VR	Blood	1995	PMID: 7579394
https://erepo.clinicalgenome.org/evrepo/ui/interpretation/a3bad0b0-ae42-494c-80b7-726b05fbbd9e	-	-	-	-

Text-mined citations for rs1800297 ...

These citations are identified by LitVar using the rs number, so they may include citations for more than one variant at this location. Please review the LitVar results carefully for your variant of interest.

Record last updated Dec 28, 2024

ClinVar Genomic variation as it relates to human health

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

Variant Details

Genes

Conditions - Germline

Submissions - Germline

Germline Functional Evidence

Citations for germline classification of this variant

Text-mined citations for rs1800297 ...