ClinVar Genomic variation as it relates to human health
NM_001114753.3(ENG):c.1465C>T (p.Gln489Ter)
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.
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.
No data submitted for somatic clinical impact
No data submitted for oncogenicity
Variant Details
- Identifiers
-
NM_001114753.3(ENG):c.1465C>T (p.Gln489Ter)
Variation ID: 383511 Accession: VCV000383511.15
- Type and length
-
single nucleotide variant, 1 bp
- Location
-
Cytogenetic: 9q34.11 9: 127818341 (GRCh38) [ NCBI UCSC ] 9: 130580620 (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 Mar 8, 2017 May 1, 2024 Mar 30, 2023 - HGVS
-
Nucleotide Protein Molecular
consequenceNM_001114753.3:c.1465C>T MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_001108225.1:p.Gln489Ter nonsense NM_000118.4:c.1465C>T NP_000109.1:p.Gln489Ter nonsense NM_001278138.2:c.919C>T NP_001265067.1:p.Gln307Ter nonsense NR_136302.1:n.1408G>A non-coding transcript variant NC_000009.12:g.127818341G>A NC_000009.11:g.130580620G>A NG_009551.1:g.41428C>T LRG_589:g.41428C>T LRG_589t1:c.1465C>T LRG_589p1:p.Gln489Ter LRG_589t2:c.1465C>T LRG_589p2:p.Gln489Ter - Protein change
- Q489*, Q307*
- Other names
- -
- Canonical SPDI
- NC_000009.12:127818340:G:A
-
Functional
consequence HelpThe effect of the variant on RNA or protein function, based on experimental evidence from submitters.
-
-
Global minor allele
frequency (GMAF) HelpThe 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.
-
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 | ||
---|---|---|---|---|---|---|
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 |
1082 | 1584 | |
LOC102723566 | - | - | - | GRCh38 | - | 480 |
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. |
---|---|---|---|---|
Likely pathogenic (1) |
criteria provided, single submitter
|
Feb 9, 2016 | RCV000421678.2 | |
Pathogenic (1) |
criteria provided, single submitter
|
Aug 27, 2021 | RCV000808225.7 | |
Pathogenic (2) |
criteria provided, multiple submitters, no conflicts
|
Mar 30, 2023 | RCV002225104.4 | |
Pathogenic (1) |
criteria provided, single submitter
|
Jun 29, 2021 | RCV002392990.2 |
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. |
|
---|---|---|---|---|---|
Likely pathogenic
(Feb 09, 2016)
|
criteria provided, single submitter
Method: clinical testing
|
Not Provided
Affected status: yes
Allele origin:
germline
|
GeneDx
Accession: SCV000523923.4
First in ClinVar: Mar 08, 2017 Last updated: Mar 08, 2017 |
Comment:
The Q489X variant in the ENG gene has not been reported as a pathogenic variant nor as a benign variant to our knowledge. Q489X is … (more)
The Q489X variant in the ENG gene has not been reported as a pathogenic variant nor as a benign variant to our knowledge. Q489X is predicted to cause loss of normal protein function either by protein truncation or nonsense-mediated mRNA decay. Multiple other downstream nonsense variants in the ENG gene have been reported in HGMD in association with HHT (Stenson et al., 2014). Furthermore, the Q489X likely pathogenic variant was not observed in approximately 6,500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, indicating it is not a common benign variant in these populations. (less)
|
|
Pathogenic
(May 06, 2021)
|
criteria provided, single submitter
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: SCV002767224.1
First in ClinVar: Dec 24, 2022 Last updated: Dec 24, 2022 |
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 (MIM#187300). Loss-of-function variants have been reported, 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 NMD-predicted variants comparable to the one identified in this case have very strong previous evidence for pathogenicity. These variants have been reported multiple times as pathogenic, and have been observed in many individuals with hereditary hemorrhagic telangiectasia (HHT) (DECIPHER, PMID: 20414677). (SP) 0802 - This variant has moderate previous evidence of pathogenicity in unrelated individuals. This variant has been reported as likely pathogenic and pathogenic, and has been observed in several individuals with HHT, or epistaxis and telangiectasia (ClinVar, LOVD, PMID: 20414677, PMID: 20719417). (SP) 1208 - Inheritance information for this variant is not currently available in this individual. (I) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign (less)
|
|
Pathogenic
(Aug 27, 2021)
|
criteria provided, single submitter
Method: clinical testing
|
Hereditary hemorrhagic telangiectasia
Affected status: unknown
Allele origin:
germline
|
Invitae
Accession: SCV000948321.4
First in ClinVar: Aug 14, 2019 Last updated: Feb 14, 2024 |
Comment:
For these reasons, this variant has been classified as Pathogenic. Loss-of-function variants in ENG are known to be pathogenic (PMID: 15879500, 20656886, 22385575). This variant … (more)
For these reasons, this variant has been classified as Pathogenic. Loss-of-function variants in ENG are known to be pathogenic (PMID: 15879500, 20656886, 22385575). This variant has been observed to segregate with hereditary hemorrhagic telangiectasia in a family (Invitae). ClinVar contains an entry for this variant (Variation ID: 383511). This variant is not present in population databases (ExAC no frequency). This sequence change creates a premature translational stop signal (p.Gln489*) in the ENG gene. It is expected to result in an absent or disrupted protein product. (less)
|
|
Pathogenic
(Mar 30, 2023)
|
criteria provided, single submitter
Method: clinical testing
|
Telangiectasia, hereditary hemorrhagic, type 1
Affected status: yes
Allele origin:
germline
|
Molecular Genetics, Royal Melbourne Hospital
Additional submitter:
Shariant Australia, Australian Genomics
Accession: SCV002503791.2
First in ClinVar: Apr 28, 2022 Last updated: Apr 15, 2024 |
Comment:
This sequence change creates a premature termination codon at position 489 in exon 12 (of 15) of ENG (p.(Gln489*)). This is predicted to result in … (more)
This sequence change creates a premature termination codon at position 489 in exon 12 (of 15) of ENG (p.(Gln489*)). This is predicted to result in an absent or disrupted protein product through nonsense mediated decay. Loss of function is a well established disease mechanism for this gene (PVS1). The variant is absent in a large population cohort (PM2, rs1057521648, gnomAD v2.1.1 and v3). The variant has been reported in two unrelated individuals with a clinical diagnosis of hereditary haemorrhagic telangiectasia (PS4_Moderate, PMID: 20414677, 20719417) and is reported to segregate with disease in an affected family (Invitae, ClinVar). Based on the classification scheme RMH ACMG Guidelines v1.2.1, this variant is classified as PATHOGENIC. The following criteria are met: PVS1, PM2, PS4_Moderate. (less)
|
|
Pathogenic
(Jun 29, 2021)
|
criteria provided, single submitter
Method: clinical testing
|
Cardiovascular phenotype
Affected status: unknown
Allele origin:
germline
|
Ambry Genetics
Accession: SCV002697458.2
First in ClinVar: Nov 29, 2022 Last updated: May 01, 2024 |
Comment:
The p.Q489* pathogenic mutation (also known as c.1465C>T), located in coding exon 12 of the ENG gene, results from a C to T substitution at … (more)
The p.Q489* pathogenic mutation (also known as c.1465C>T), located in coding exon 12 of the ENG gene, results from a C to T substitution at nucleotide position 1465. This changes the amino acid from a glutamine to a stop codon within coding exon 12. This mutation has been reported in individuals with hereditary hemorrhagic telangiectasia (Richards-Yutz J et al. Hum Genet, 2010 Jul;128:61-77; Corre P et al. Br J Oral Maxillofac Surg, 2011 Jul;49:e9-11). In addition to the clinical data presented in the literature, this alteration is expected to result in loss of function by premature protein truncation or nonsense-mediated mRNA decay. As such, this alteration is interpreted as a disease-causing mutation. (less)
|
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. |
Citations for germline classification of this variant
HelpTitle | Author | Journal | Year | Link |
---|---|---|---|---|
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 |
A novel ENG mutation causing impaired co-translational processing of endoglin associated with hereditary hemorrhagic telangiectasia. | Suzuki A | Thrombosis research | 2012 | PMID: 22385575 |
A brain abscess following dental extractions in a patient with hereditary hemorrhagic telangiectasia. | Corre P | The British journal of oral & maxillofacial surgery | 2011 | PMID: 20719417 |
The physiological role of endoglin in the cardiovascular system. | López-Novoa JM | American journal of physiology. Heart and circulatory physiology | 2010 | PMID: 20656886 |
Update on molecular diagnosis of hereditary hemorrhagic telangiectasia. | Richards-Yutz J | Human genetics | 2010 | PMID: 20414677 |
Hereditary haemorrhagic telangiectasia: current views on genetics and mechanisms of disease. | Abdalla SA | Journal of medical genetics | 2006 | PMID: 15879500 |
Text-mined citations for rs1057521648 ...
HelpRecord last updated May 01, 2024
This date represents the last time this VCV record was updated. The update may be due to an update to one of the included submitted records (SCVs), or due to an update that ClinVar made to the variant such as adding HGVS expressions or a rs number. So this date may be different from the date of the “most recent submission” reported at the top of this page.