VCV002775447.2 - ClinVar

NM_000132.4(F8):c.5488G>T (p.Glu1830Ter)

Germline

Top reviewed classifications are shown here.

Submission summary:

1 submission

1 submitter

1 condition

Reviewed by expert panel

Pathogenic

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.5488G>T (p.Glu1830Ter)

Variation ID: 2775447 Accession: VCV002775447.2

Type and length

single nucleotide variant, 1 bp

Location

Cytogenetic: Xq28 X: 154904909 (GRCh38) [ NCBI UCSC ] X: 154133184 (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	Feb 14, 2024	Jun 23, 2024	Feb 2, 2024

HGVS

Nucleotide	Protein	Molecular consequence
NM_000132.4:c.5488G>T MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.	NP_000123.1:p.Glu1830Ter	nonsense
NC_000023.11:g.154904909C>A
NC_000023.10:g.154133184C>A
NG_011403.2:g.122815G>T
LRG_555:g.122815G>T
LRG_555t1:c.5488G>T	LRG_555p1:p.Glu1830Ter

... more HGVS ... less HGVS

Protein change

E1830*

Other names

NM_000132.3:c.5488G>T

Canonical SPDI

NC_000023.11:154904908:C:A

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.

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

Links

VarSome

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	958	1234

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	Pathogenic (1)	reviewed by expert panel	Feb 2, 2024	RCV003510975.2

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.
Pathogenic (Feb 02, 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: SCV004363657.2 First in ClinVar: Feb 14, 2024 Last updated: Jun 23, 2024	Other databases https://erepo.clinicalgenome.org… https://erepo.clinicalgenome.org/evrepo/ui/interpretation/0d2036b6-1d6d-4816-9b31-cf27fc6d6a86 Comment: The c.5488G>T (p.Glu1830Ter) variant is a nonsense variant that is predicted to introduce a premature stop codon in exon 16/26 and expected to result in … (more) The c.5488G>T (p.Glu1830Ter) variant is a nonsense variant that is predicted to introduce a premature stop codon in exon 16/26 and expected to result in nonsense-mediated mRNA decay, so PVS1 criteria is met. This variant is absent from males in population databases (gnomAD v2.1.1/gnomAD v3), which meets PM2_Supporting criteria. The c.5488G>T (p.Glu1830Ter) variant is not reported in patients with Hemophilia A in the literature to the best of our knowledge; however 1 patient with severe hemophilia A is reported from internal laboratory data. 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/F9: PVS1, PM2_Supporting, PS4_Supporting. (less)

Comment:

The c.5488G>T (p.Glu1830Ter) variant is a nonsense variant that is predicted to introduce a premature stop codon in exon 16/26 and expected to result in nonsense-mediated mRNA decay, so PVS1 criteria is met. This variant is absent from males in population databases (gnomAD v2.1.1/gnomAD v3), which meets PM2_Supporting criteria. The c.5488G>T (p.Glu1830Ter) variant is not reported in patients with Hemophilia A in the literature to the best of our knowledge; however 1 patient with severe hemophilia A is reported from internal laboratory data. 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/F9: PVS1, PM2_Supporting, PS4_Supporting.

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
https://erepo.clinicalgenome.org/evrepo/ui/interpretation/0d2036b6-1d6d-4816-9b31-cf27fc6d6a86	-	-	-	-

Text-mined citations for this variant ...

Record last updated Oct 27, 2024

ClinVar Genomic variation as it relates to human health

NM_000132.4(F8):c.5488G>T (p.Glu1830Ter)

Variant Details

Genes

Conditions - Germline

Submissions - Germline

Germline Functional Evidence

Citations for germline classification of this variant

Text-mined citations for this variant ...