VCV002034993.4 - ClinVar

NM_001114753.3(ENG):c.392dup (p.Val133fs)

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.

(3)

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, multiple submitters, no conflicts

Somatic

No data submitted for somatic clinical impact

Somatic

No data submitted for oncogenicity

Variant Details

Identifiers

NM_001114753.3(ENG):c.392dup (p.Val133fs)

Variation ID: 2034993 Accession: VCV002034993.4

Type and length

Duplication, 1 bp

Location

Cytogenetic: 9q34.11 9: 127826640-127826641 (GRCh38) [ NCBI UCSC ] 9: 130588919-130588920 (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 8, 2023	Oct 8, 2024	Dec 17, 2023

HGVS

Nucleotide	Protein	Molecular consequence
NM_001114753.3:c.392dup MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.	NP_001108225.1:p.Val133fs	frameshift
NM_000118.3:c.392dupC
NM_000118.4:c.388dup	NP_000109.1:p.Val133Glyfs	frameshift
NM_001114753.2:c.392dup
NM_001278138.2:c.-155dup		5 prime UTR
NM_001406715.1:c.388dup	NP_001393644.1:p.Val133Glyfs	frameshift
NC_000009.12:g.127826645dup
NC_000009.11:g.130588924dup
NG_009551.1:g.33128dup
NG_117586.1:g.794dup
LRG_589:g.33128dup
LRG_589t1:c.392dup	LRG_589p1:p.Val133fs
LRG_589t2:c.388dup	LRG_589p2:p.Val133Glyfs

... more HGVS ... less HGVS

Protein change

V133fs

Other names

p.Val133Glyfs*16

Canonical SPDI

NC_000009.12:127826640:GGGGG:GGGGGG

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.
ENG		Sufficient evidence for dosage pathogenicity	No evidence available	GRCh38 GRCh37	1106	1618

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 hemorrhagic telangiectasia	Pathogenic (1)	criteria provided, single submitter	Dec 17, 2023	RCV002877287.3
not provided	Pathogenic (1)	criteria provided, single submitter	Feb 8, 2022	RCV003481341.1
ENG-related disorder	Likely pathogenic (1)	no assertion criteria provided	Sep 22, 2024	RCV004753584.1

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 08, 2022)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Not provided Affected status: unknown Allele origin: germline	Mayo Clinic Laboratories, Mayo Clinic Accession: SCV004226820.1 First in ClinVar: Jan 06, 2024 Last updated: Jan 06, 2024	Comment: PP4, PM2, PVS1 Number of individuals with the variant: 1
Pathogenic (Dec 17, 2023)	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015)) Method: clinical testing	Hereditary hemorrhagic telangiectasia Affected status: unknown Allele origin: germline	Labcorp Genetics (formerly Invitae), Labcorp Accession: SCV003241391.2 First in ClinVar: Feb 07, 2023 Last updated: Feb 20, 2024	Publications: PubMed (1) PubMed: 15879500 Comment: This sequence change creates a premature translational stop signal (p.Val133Glyfs16) in the ENG gene. It is expected to result in an absent or disrupted protein … (more) This sequence change creates a premature translational stop signal (p.Val133Glyfs16) in the ENG gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in ENG are known to be pathogenic (PMID: 15879500). This variant is not present in population databases (gnomAD no frequency). This variant has not been reported in the literature in individuals affected with ENG-related conditions. ClinVar contains an entry for this variant (Variation ID: 2034993). For these reasons, this variant has been classified as Pathogenic. (less)
Likely pathogenic (Sep 22, 2024)	no assertion criteria provided Method: clinical testing	ENG-related condition Affected status: unknown Allele origin: germline	PreventionGenetics, part of Exact Sciences Accession: SCV005362633.1 First in ClinVar: Oct 08, 2024 Last updated: Oct 08, 2024	Comment: The ENG c.392dupC variant is predicted to result in a frameshift and premature protein termination (p.Val133Glyfs16). To our knowledge, this variant has not been reported … (more) The ENG c.392dupC variant is predicted to result in a frameshift and premature protein termination (p.Val133Glyfs16). To our knowledge, this variant has not been reported in the literature or a large population database, indicating this variant is rare. Frameshift variants in ENG are expected to be pathogenic. This variant is interpreted as likely pathogenic. (less)

Comment:

This sequence change creates a premature translational stop signal (p.Val133Glyfs*16) in the ENG gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in ENG are known to be pathogenic (PMID: 15879500). This variant is not present in population databases (gnomAD no frequency). This variant has not been reported in the literature in individuals affected with ENG-related conditions. ClinVar contains an entry for this variant (Variation ID: 2034993). For these reasons, this variant has been classified as Pathogenic.

Comment:

The ENG c.392dupC variant is predicted to result in a frameshift and premature protein termination (p.Val133Glyfs*16). To our knowledge, this variant has not been reported in the literature or a large population database, indicating this variant is rare. Frameshift variants in ENG are expected to be pathogenic. This variant is interpreted as likely pathogenic.

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
Hereditary haemorrhagic telangiectasia: current views on genetics and mechanisms of disease.	Abdalla SA	Journal of medical genetics	2006	PMID: 15879500

Text-mined citations for this variant ...

Record last updated Oct 13, 2024

ClinVar Genomic variation as it relates to human health

NM_001114753.3(ENG):c.392dup (p.Val133fs)

Variant Details

Genes

Conditions - Germline

Submissions - Germline

Germline Functional Evidence

Citations for germline classification of this variant

Text-mined citations for this variant ...