VCV003075947.1 - ClinVar

NM_004444.5(EPHB4):c.2424dup (p.Val809fs)

Germline

Classification

The aggregate germline classification for this variant, typically for a monogenic or Mendelian disorder as in the ACMG/AMP guidelines, or for response to a drug. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the aggregate classification.

(1)

Stars represent the aggregate review status, or the level of review supporting the aggregate germline classification for this VCV record. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the review status. The number of submissions which contribute to this review status is shown in parentheses.

Pathogenic

criteria provided, single submitter

Somatic

No data submitted for somatic clinical impact

Somatic

No data submitted for oncogenicity

Variant Details

Identifiers

NM_004444.5(EPHB4):c.2424dup (p.Val809fs)

Variation ID: 3075947 Accession: VCV003075947.1

Type and length

Duplication, 1 bp

Location

Cytogenetic: 7q22.1 7: 100806479-100806480 (GRCh38) [ NCBI UCSC ] 7: 100404101-100404102 (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	Apr 20, 2024	Apr 20, 2024	Feb 9, 2024

HGVS

Nucleotide	Protein	Molecular consequence
NM_004444.5:c.2424dup MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.	NP_004435.3:p.Val809fs	frameshift
NC_000007.14:g.100806481dup
NC_000007.13:g.100404103dup
NG_052671.1:g.26042dup
NG_084625.2:g.1139dup

... more HGVS ... less HGVS

Protein change

V809fs

Other names

Canonical SPDI

NC_000007.14:100806479:AA:AAA

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.
EPHB4		-	-	GRCh38 GRCh37	650	802
LOC126860124	-	-	-	GRCh38	-	105

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.
Capillary malformation-arteriovenous malformation syndrome	Pathogenic (1)	criteria provided, single submitter	Feb 9, 2024	RCV004018265.2

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 09, 2024)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Capillary malformation-arteriovenous malformation syndrome (Autosomal dominant inheritance) Affected status: unknown Allele origin: germline	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine Accession: SCV004847289.1 First in ClinVar: Apr 20, 2024 Last updated: Apr 20, 2024	Comment: The p.Val809CysfsX26 variant in EPHB4 was identified through WGS analysis in an adult with liver arteriovenous malformation, skin telangiectasias, and epistaxis by the Broad Institute … (more) The p.Val809CysfsX26 variant in EPHB4 was identified through WGS analysis in an adult with liver arteriovenous malformation, skin telangiectasias, and epistaxis by the Broad Institute Rare Genomes Project. It was absent from large population studies. This variant is predicted to cause a frameshift, which alters the protein’s amino acid sequence beginning at position 809 and leads to a premature termination codon 26 amino acids downstream. This alteration is then predicted to lead to a truncated or absent protein. Loss of function of the EPHB4 gene is an established disease mechanism in autosomal dominant CM-AVM. In summary, this variant meets criteria to be classified as pathogenic for autosomal dominant CM-AVM. ACMG/AMP Criteria applied: PVS1, PS4_Supporting, PM2_Supporting. (less)

Comment:

The p.Val809CysfsX26 variant in EPHB4 was identified through WGS analysis in an adult with liver arteriovenous malformation, skin telangiectasias, and epistaxis by the Broad Institute Rare Genomes Project. It was absent from large population studies. This variant is predicted to cause a frameshift, which alters the protein’s amino acid sequence beginning at position 809 and leads to a premature termination codon 26 amino acids downstream. This alteration is then predicted to lead to a truncated or absent protein. Loss of function of the EPHB4 gene is an established disease mechanism in autosomal dominant CM-AVM. In summary, this variant meets criteria to be classified as pathogenic for autosomal dominant CM-AVM. ACMG/AMP Criteria applied: PVS1, PS4_Supporting, PM2_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

There are no citations for germline classification of this variant in ClinVar. If you know of citations for this variation, please consider submitting that information to ClinVar.

Text-mined citations for this variant ...

Record last updated Jun 23, 2024

ClinVar Genomic variation as it relates to human health

NM_004444.5(EPHB4):c.2424dup (p.Val809fs)

Variant Details

Genes

Conditions - Germline

Submissions - Germline

Germline Functional Evidence

Citations for germline classification of this variant

Text-mined citations for this variant ...