ClinVar Genomic variation as it relates to human health
NM_001114753.3(ENG):c.1273-2A>G
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
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NM_001114753.3(ENG):c.1273-2A>G
Variation ID: 162498 Accession: VCV000162498.23
- Type and length
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single nucleotide variant, 1 bp
- Location
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Cytogenetic: 9q34.11 9: 127819662 (GRCh38) [ NCBI UCSC ] 9: 130581941 (GRCh37) [ NCBI UCSC ]
- Timeline in ClinVar
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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 Jan 18, 2015 May 1, 2024 Feb 13, 2024 - HGVS
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Nucleotide Protein Molecular
consequenceNM_001114753.3:c.1273-2A>G MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
splice acceptor NM_000118.4:c.1273-2A>G splice acceptor NM_001114753.1:c.1273-2A>G NM_001278138.2:c.727-2A>G splice acceptor NC_000009.12:g.127819662T>C NC_000009.11:g.130581941T>C NG_009551.1:g.40107A>G LRG_589:g.40107A>G LRG_589t1:c.1273-2A>G - Protein change
- Other names
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- Canonical SPDI
- NC_000009.12:127819661:T:C
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Functional
consequence HelpThe effect of the variant on RNA or protein function, based on experimental evidence from submitters.
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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.
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Allele frequency
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The frequency of the allele represented by this VCV record.
The Genome Aggregation Database (gnomAD), exomes 0.00000
Exome Aggregation Consortium (ExAC) 0.00001
Trans-Omics for Precision Medicine (TOPMed) 0.00001
NHLBI Exome Sequencing Project (ESP) Exome Variant Server 0.00008
Genes
Gene | OMIM | ClinGen Gene Dosage Sensitivity Curation |
Variation Viewer
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Links to Variation Viewer, a genome browser to view variation data from NCBI databases. |
Related variants | ||
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HI score
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The haploinsufficiency score for the gene, curated by ClinGen’s Dosage Sensitivity Curation task team. |
TS score
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The triplosensitivity score for the gene, curated by ClinGen’s Dosage Sensitivity Curation task team. |
Within gene
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The number of variants in ClinVar that are contained within this gene, with a link to view the list of variants. |
All
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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. |
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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
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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
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The most recent date that a submitter evaluated this variant for the condition. |
Variation/condition record
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The RCV accession number, with most recent version number, for the variant-condition record, with a link to the RCV web page. |
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Pathogenic (1) |
no assertion criteria provided
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Jun 1, 2014 | RCV000149883.3 | |
Pathogenic (1) |
criteria provided, single submitter
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Apr 7, 2016 | RCV000256118.2 | |
Pathogenic (1) |
criteria provided, single submitter
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Apr 24, 2023 | RCV000791417.9 | |
Pathogenic (1) |
criteria provided, single submitter
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Feb 13, 2024 | RCV002371992.2 | |
Pathogenic (1) |
criteria provided, single submitter
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Mar 8, 2017 | RCV000508197.8 | |
Pathogenic/Likely pathogenic (3) |
criteria provided, multiple submitters, no conflicts
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Nov 24, 2021 | RCV000679898.7 |
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
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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
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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. |
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Pathogenic
(Mar 08, 2017)
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criteria provided, single submitter
Method: clinical testing
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not specified
Affected status: unknown
Allele origin:
germline
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ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories
Accession: SCV000603480.1
First in ClinVar: Sep 30, 2017 Last updated: Sep 30, 2017 |
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Pathogenic
(Apr 07, 2016)
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criteria provided, single submitter
Method: clinical testing
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Not Provided
Affected status: yes
Allele origin:
germline
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GeneDx
Accession: SCV000322194.6
First in ClinVar: Oct 10, 2016 Last updated: Oct 10, 2016 |
Comment:
The c.1273-2 A>G pathogenic variant has been reported in one individual with a clinical diagnosis of HHT who presented with pulmonary arteriovenous malformations (AVMs), epistaxis, … (more)
The c.1273-2 A>G pathogenic variant has been reported in one individual with a clinical diagnosis of HHT who presented with pulmonary arteriovenous malformations (AVMs), epistaxis, telangiectasias and a positive family history (Bossler et al., 2006); however, no additional information regarding other affected family members was provided. This variant destroys the canonical splice acceptor site in intron 9 and is predicted to cause abnormal gene splicing. This variant is predicted to lead to either an abnormal message that is subject to nonsense-mediated mRNA decay, or to an abnormal protein product if the message is used for protein translation. Many other downstream splice site variants in the ENG gene have been reported in HGMD in association with HHT (Stenson et al., 2014). Furthermore, the c.1273-2 A>G variant was not observed with any significant frequency 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.In summary, c.1273-2 A>G in the ENG gene is interpreted as a pathogenic variant. (less)
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Pathogenic
(Sep 01, 2017)
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criteria provided, single submitter
Method: clinical testing
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Telangiectasia, hereditary hemorrhagic, type 1
(Autosomal dominant inheritance)
Affected status: yes
Allele origin:
maternal
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Baylor Genetics
Accession: SCV000807322.2
First in ClinVar: Sep 17, 2018 Last updated: Dec 11, 2022 |
Comment:
This mutation has been previously reported as disease-causing and was found once in our laboratory maternally inherited in a 2-year-old male with bloody vomit and … (more)
This mutation has been previously reported as disease-causing and was found once in our laboratory maternally inherited in a 2-year-old male with bloody vomit and poor gut motility, in addition to motor delays, short stature microcephly, polymicrogyria vs. cortical malformation. (less)
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Pathogenic
(Apr 24, 2023)
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criteria provided, single submitter
Method: clinical testing
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Hereditary hemorrhagic telangiectasia
Affected status: unknown
Allele origin:
germline
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Invitae
Accession: SCV000814864.7
First in ClinVar: Oct 10, 2018 Last updated: Feb 28, 2024 |
Comment:
For these reasons, this variant has been classified as Pathogenic. Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this … (more)
For these reasons, this variant has been classified as Pathogenic. Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. ClinVar contains an entry for this variant (Variation ID: 162498). Disruption of this splice site has been observed in individuals with ENG-related disease (PMID: 16752392; Invitae). This variant is present in population databases (rs373842615, gnomAD 0.0009%). This sequence change affects an acceptor splice site in intron 9 of the ENG gene. It is expected to disrupt RNA splicing. Variants that disrupt the donor or acceptor splice site typically lead to a loss of protein function (PMID: 16199547), and loss-of-function variants in ENG are known to be pathogenic (PMID: 15879500). (less)
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Pathogenic
(Feb 13, 2024)
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criteria provided, single submitter
Method: clinical testing
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Cardiovascular phenotype
Affected status: unknown
Allele origin:
germline
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Ambry Genetics
Accession: SCV002686027.2
First in ClinVar: Nov 29, 2022 Last updated: May 01, 2024 |
Comment:
The c.1273-2A>G intronic variant results from an A to G substitution two nucleotides before coding exon 10 of the ENG gene. Alterations that disrupt the … (more)
The c.1273-2A>G intronic variant results from an A to G substitution two nucleotides before coding exon 10 of the ENG gene. Alterations that disrupt the canonical splice site are expected to cause aberrant splicing, resulting in an abnormal protein or a transcript that is subject to nonsense-mediated mRNA decay; however, direct evidence is unavailable. The exact functional effect of the altered amino acid sequence is unknown. Based on data from gnomAD, the G allele has an overall frequency of <0.001% (1/238470) total alleles studied. The highest observed frequency was 0.001% (1/107270) of European (non-Finnish) alleles. This variant has been described in patients meeting diagnostic criteria for hereditary hemorrhagic telangiectasia (HHT) (Bossler, 2006; Ambry internal data). This nucleotide position is highly conserved in available vertebrate species. In silico splice site analysis predicts that this alteration will weaken the native splice acceptor site. Based on the available evidence, this alteration is classified as pathogenic. (less)
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Likely pathogenic
(Nov 24, 2021)
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criteria provided, single submitter
Method: clinical testing
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Telangiectasia, hereditary hemorrhagic, type 1
Affected status: unknown
Allele origin:
unknown
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Fulgent Genetics, Fulgent Genetics
Accession: SCV002798196.1
First in ClinVar: Dec 31, 2022 Last updated: Dec 31, 2022 |
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Pathogenic
(Jun 01, 2014)
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no assertion criteria provided
Method: research
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Haemorrhagic telangiectasia 1
(Autosomal dominant inheritance)
Affected status: unknown
Allele origin:
germline
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CSER _CC_NCGL, University of Washington
Study: ESP 6500 variant annotation
Accession: SCV000190185.1 First in ClinVar: Jan 18, 2015 Last updated: Jan 18, 2015
Comment:
Variants classified for the Actionable exomic incidental findings in 6503 participants: challenges of variant classification manuscript
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not provided
(-)
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no classification provided
Method: phenotyping only
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Telangiectasia, hereditary hemorrhagic, type 1
Affected status: unknown
Allele origin:
maternal
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GenomeConnect - Brain Gene Registry
Accession: SCV004804573.1
First in ClinVar: Mar 30, 2024 Last updated: Mar 30, 2024 |
Comment:
Variant classified as Pathogenic and reported on 11-19-2020 by USAF Medical Genetics Center. Assertions are reported exactly as they appear on the patient provided laboratory … (more)
Variant classified as Pathogenic and reported on 11-19-2020 by USAF Medical Genetics Center. Assertions are reported exactly as they appear on the patient provided laboratory report. GenomeConnect does not attempt to reinterpret the variant. The IDDRC-CTSA National Brain Gene Registry (BGR) is a study funded by the U.S. National Center for Advancing Translational Sciences (NCATS) and includes 13 Intellectual and Developmental Disability Research Center (IDDRC) institutions. The study is led by Principal Investigator Dr. Philip Payne from Washington University. The BGR is a data commons of gene variants paired with subject clinical information. This database helps scientists learn more about genetic changes and their impact on the brain and behavior. Participation in the Brain Gene Registry requires participation in GenomeConnect. More information about the Brain Gene Registry can be found on the study website - https://braingeneregistry.wustl.edu/. (less)
Clinical Features:
Autism (present) , Neurodevelopmental delay (present) , Cafe au lait spots, multiple (present)
Indication for testing: Diagnostic
Age: 0-9 years
Sex: male
Secondary finding: yes
Method: Exome Sequencing
Testing laboratory: Defense Health Agency Genetics Reference Laboratory, United States Air Force
Date variant was reported to submitter: 2020-11-19
Testing laboratory interpretation: Pathogenic
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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 |
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Novel mutations in ENG and ACVRL1 identified in a series of 200 individuals undergoing clinical genetic testing for hereditary hemorrhagic telangiectasia (HHT): correlation of genotype with phenotype. | Bossler AD | Human mutation | 2006 | PMID: 16752392 |
Hereditary haemorrhagic telangiectasia: current views on genetics and mechanisms of disease. | Abdalla SA | Journal of medical genetics | 2006 | PMID: 15879500 |
Splicing in action: assessing disease causing sequence changes. | Baralle D | Journal of medical genetics | 2005 | PMID: 16199547 |
Text-mined citations for rs373842615 ...
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.