VCV000949536.12 - ClinVar

NM_001114753.3(ENG):c.774C>A (p.Tyr258Ter)

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.

(4)

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.774C>A (p.Tyr258Ter)

Variation ID: 949536 Accession: VCV000949536.12

Type and length

single nucleotide variant, 1 bp

Location

Cytogenetic: 9q34.11 9: 127825273 (GRCh38) [ NCBI UCSC ] 9: 130587552 (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	Jul 16, 2020	Apr 6, 2024	Mar 25, 2024

HGVS

Nucleotide	Protein	Molecular consequence
NM_001114753.3:c.774C>A MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.	NP_001108225.1:p.Tyr258Ter	nonsense
NM_000118.4:c.774C>A	NP_000109.1:p.Tyr258Ter	nonsense
NM_001278138.2:c.228C>A	NP_001265067.1:p.Tyr76Ter	nonsense
NM_001406715.1:c.774C>A	NP_001393644.1:p.Tyr258Ter	nonsense
NC_000009.12:g.127825273G>T
NC_000009.11:g.130587552G>T
NG_009551.1:g.34496C>A
LRG_589:g.34496C>A
LRG_589t1:c.774C>A	LRG_589p1:p.Tyr258Ter
LRG_589t2:c.774C>A	LRG_589p2:p.Tyr258Ter

... more HGVS ... less HGVS

Protein change

Y76*, Y258*

Other names

Canonical SPDI

NC_000009.12:127825272:G:T

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.

0.00040 (A)

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

Links

dbSNP: rs537154767 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	1101	1612

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	Jun 26, 2022	RCV001221010.8
Telangiectasia, hereditary hemorrhagic, type 1	Pathogenic (3)	criteria provided, multiple submitters, no conflicts	Mar 25, 2024	RCV001262072.5

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 (Jan 01, 2018)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: research	Telangiectasia, hereditary hemorrhagic, type 1 Affected status: yes Allele origin: unknown	NIHR Bioresource Rare Diseases, University of Cambridge Accession: SCV001439456.1 First in ClinVar: Oct 30, 2020 Last updated: Oct 30, 2020	Publications: PubMed (1) PubMed: 32573726 Comment: PVS1+PM2+PP4 Number of individuals with the variant: 1
Pathogenic (Feb 02, 2022)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Telangiectasia, hereditary hemorrhagic, type 1 (Autosomal dominant inheritance) Affected status: unknown Allele origin: germline	Victorian Clinical Genetics Services, Murdoch Childrens Research Institute Additional submitter: Shariant Australia, Australian Genomics Accession: SCV002769116.1 First in ClinVar: Dec 24, 2022 Last updated: Dec 24, 2022	Publications: PubMed (3) PubMed: 24001356‚ 25312062‚ 34377910 Comment: Based on the classification scheme VCGS_Germline_v1.3.4, this variant is classified as Pathogenic. Following criteria are met: 0103 - Dominant negative and loss of function are … (more) Based on the classification scheme VCGS_Germline_v1.3.4, this variant is classified as Pathogenic. Following criteria are met: 0103 - Dominant negative and loss of function are known mechanisms of disease in this gene and are associated with hereditary hemorrhagic telangiectasia type 1 (HHT; MIM#187300). Protein truncating variants have been associated with loss of function, while missense variants have been demonstrated to have both loss of function and dominant negative effects on protein activity (PMID: 25312062) (I). 0107 - This gene is associated with autosomal dominant disease. (I) 0201 - Variant is predicted to cause nonsense-mediated decay (NMD) and loss of protein (premature termination codon is located at least 54 nucleotides upstream of the final exon-exon junction). (SP) 0251 - This variant is heterozygous. (I) 0301 - Variant is absent from gnomAD (both v2 and v3). (SP) 0701 - Other variants predicted to cause NMD comparable to the one identified in this case have very strong previous evidence for pathogenicity (DECIPHER). (SP) 0802 - This variant has moderate previous evidence of pathogenicity in unrelated individuals. It has been reported as pathogenic in ClinVar and also confirmed the clinical diagnosis of HHT in a Danish individual (PMID: 24001356). In addition, it was reported de novo in an individual with pulmonary arteriovenous malformations, thought to be the first manifestation of HHT (PMID: 34377910). (SP) 1205 - This variant has been shown to be maternally inherited (by an external laboratory). (I) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign (less)
Pathogenic (Jun 26, 2022)	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: SCV001393028.5 First in ClinVar: Jul 16, 2020 Last updated: Feb 14, 2024	Publications: PubMed (2) PubMed: 24001356‚ 15879500 Comment: For these reasons, this variant has been classified as Pathogenic. ClinVar contains an entry for this variant (Variation ID: 949536). This premature translational stop signal … (more) For these reasons, this variant has been classified as Pathogenic. ClinVar contains an entry for this variant (Variation ID: 949536). This premature translational stop signal has been observed in individuals with hereditary hemorrhagic telangiectasia (PMID: 24001356; Invitae). This variant is not present in population databases (gnomAD no frequency). This sequence change creates a premature translational stop signal (p.Tyr258*) 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). (less)
Pathogenic (Mar 25, 2024)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Telangiectasia, hereditary hemorrhagic, type 1 Affected status: unknown Allele origin: germline	Center for Genomic Medicine, King Faisal Specialist Hospital and Research Center Accession: SCV004806268.1 First in ClinVar: Apr 06, 2024 Last updated: Apr 06, 2024

Comment:

Based on the classification scheme VCGS_Germline_v1.3.4, this variant is classified as Pathogenic. Following criteria are met: 0103 - Dominant negative and loss of function are known mechanisms of disease in this gene and are associated with hereditary hemorrhagic telangiectasia type 1 (HHT; MIM#187300). Protein truncating variants have been associated with loss of function, while missense variants have been demonstrated to have both loss of function and dominant negative effects on protein activity (PMID: 25312062) (I). 0107 - This gene is associated with autosomal dominant disease. (I) 0201 - Variant is predicted to cause nonsense-mediated decay (NMD) and loss of protein (premature termination codon is located at least 54 nucleotides upstream of the final exon-exon junction). (SP) 0251 - This variant is heterozygous. (I) 0301 - Variant is absent from gnomAD (both v2 and v3). (SP) 0701 - Other variants predicted to cause NMD comparable to the one identified in this case have very strong previous evidence for pathogenicity (DECIPHER). (SP) 0802 - This variant has moderate previous evidence of pathogenicity in unrelated individuals. It has been reported as pathogenic in ClinVar and also confirmed the clinical diagnosis of HHT in a Danish individual (PMID: 24001356). In addition, it was reported de novo in an individual with pulmonary arteriovenous malformations, thought to be the first manifestation of HHT (PMID: 34377910). (SP) 1205 - This variant has been shown to be maternally inherited (by an external laboratory). (I) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign

Comment:

For these reasons, this variant has been classified as Pathogenic. ClinVar contains an entry for this variant (Variation ID: 949536). This premature translational stop signal has been observed in individuals with hereditary hemorrhagic telangiectasia (PMID: 24001356; Invitae). This variant is not present in population databases (gnomAD no frequency). This sequence change creates a premature translational stop signal (p.Tyr258*) 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).

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
Pulmonary arteriovenous malformation with unexplained cyanosis as the first presentation of hereditary haemorrhagic telangiectasia, case report, and literature review.	Alakhfash A	European heart journal. Case reports	2021	PMID: 34377910
Mutational and phenotypic characterization of hereditary hemorrhagic telangiectasia.	Shovlin CL	Blood	2020	PMID: 32573726
Functional analysis of endoglin mutations from hereditary hemorrhagic telangiectasia type 1 patients reveals different mechanisms for endoglin loss of function.	Mallet C	Human molecular genetics	2015	PMID: 25312062
National mutation study among Danish patients with hereditary haemorrhagic telangiectasia.	Tørring PM	Clinical genetics	2014	PMID: 24001356
Hereditary haemorrhagic telangiectasia: current views on genetics and mechanisms of disease.	Abdalla SA	Journal of medical genetics	2006	PMID: 15879500

Text-mined citations for rs537154767 ...

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 Sep 29, 2024

ClinVar Genomic variation as it relates to human health

NM_001114753.3(ENG):c.774C>A (p.Tyr258Ter)

Variant Details

Genes

Conditions - Germline

Submissions - Germline

Germline Functional Evidence

Citations for germline classification of this variant

Text-mined citations for rs537154767 ...