ClinVar Genomic variation as it relates to human health
NM_001114753.3(ENG):c.155G>A (p.Gly52Asp)
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.155G>A (p.Gly52Asp)
Variation ID: 618085 Accession: VCV000618085.12
- Type and length
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single nucleotide variant, 1 bp
- Location
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Cytogenetic: 9q34.11 9: 127843158 (GRCh38) [ NCBI UCSC ] 9: 130605437 (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 Feb 18, 2019 Feb 14, 2024 May 25, 2023 - HGVS
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Nucleotide Protein Molecular
consequenceNM_001114753.3:c.155G>A MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_001108225.1:p.Gly52Asp missense NM_000118.2:c.155G>A NM_000118.4:c.155G>A NP_000109.1:p.Gly52Asp missense NM_001278138.2:c.-392G>A 5 prime UTR NM_001406715.1:c.155G>A NP_001393644.1:p.Gly52Asp missense NC_000009.12:g.127843158C>T NC_000009.11:g.130605437C>T NG_009551.1:g.16611G>A LRG_589:g.16611G>A LRG_589t1:c.155G>A LRG_589p1:p.Gly52Asp LRG_589t2:c.155G>A LRG_589p2:p.Gly52Asp - Protein change
- G52D
- Other names
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- Canonical SPDI
- NC_000009.12:127843157:C:T
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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.
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- Links
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 |
1080 | 1577 |
Conditions - Germline
Condition
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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
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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/Likely pathogenic (2) |
criteria provided, multiple submitters, no conflicts
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May 25, 2023 | RCV000756077.10 | |
Likely pathogenic (1) |
criteria provided, single submitter
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Jan 1, 2018 | RCV001262053.3 | |
Likely pathogenic (1) |
criteria provided, single submitter
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Dec 12, 2014 | RCV002397524.1 | |
Likely pathogenic (1) |
criteria provided, single submitter
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Dec 16, 2022 | RCV003594025.1 |
Submissions - Germline
Classification
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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
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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
(Jul 09, 2017)
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criteria provided, single submitter
Method: clinical testing
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Not Provided
Affected status: unknown
Allele origin:
germline
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ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories
Accession: SCV000883793.1
First in ClinVar: Feb 18, 2019 Last updated: Feb 18, 2019 |
Comment:
The ENG c.155G>A; p.Gly52Asp variant has previously been reported in a newborn with a family history of hereditary hemorrhagic telangiectasia (HHT) symptoms (Paquet 2001), and … (more)
The ENG c.155G>A; p.Gly52Asp variant has previously been reported in a newborn with a family history of hereditary hemorrhagic telangiectasia (HHT) symptoms (Paquet 2001), and the variant was shown to have reduced expression of fully processed endoglin. In addition, other variants at this codon (Gly52Val, Gly52Arg) have been reported in families with HHT (Gallione 1998, Pece-Barbara 1999, Wehner 2006). The p.Gly52Asp variant is absent from general population databases (Exome Variant Server, Genome Aggregation Database). The glycine at codon 52 is well conserved and computational algorithms (SIFT, PolyPhen2, MutationTaster) predict this variant to be damaging to the protein. Based on the above information, this variant is considered pathogenic. REFERENCES Gallione CJ et al. Mutation and expression analysis of the endoglin gene in hereditary hemorrhagic telangiectasia reveals null alleles. Hum Mutat. 1998;11(4):286-94. Paquet ME et al. Analysis of several endoglin mutants reveals no endogenous mature or secreted protein capable of interfering with normal endoglin function. Hum Mol Genet. 2001 Jun 15;10(13):1347-57. Pece-Barbara N et al. Expression analysis of four endoglin missense mutations suggests that haploinsufficiency is the predominant mechanism for hereditary hemorrhagic telangiectasia type 1. Hum Mol Genet. 1999 Nov;8(12):2171-81. Wehner LE et al. Mutation analysis in hereditary haemorrhagic telangiectasia in Germany reveals 11 novel ENG and 12 novel ACVRL1/ALK1 mutations. Clin Genet. 2006 Mar;69(3):239-45. (less)
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Likely pathogenic
(Jan 01, 2018)
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criteria provided, single submitter
Method: research
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Telangiectasia, hereditary hemorrhagic, type 1
Affected status: yes
Allele origin:
unknown
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NIHR Bioresource Rare Diseases, University of Cambridge
Accession: SCV001439433.1
First in ClinVar: Oct 30, 2020 Last updated: Oct 30, 2020 |
Comment:
PS3+PM2+PM1+PP4+PP5
Number of individuals with the variant: 1
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Likely pathogenic
(Dec 12, 2014)
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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: SCV002708881.1
First in ClinVar: Nov 29, 2022 Last updated: Nov 29, 2022 |
Comment:
The p.G52D variant (also known as c.155G>A), located in coding exon 2 of the ENG gene, results from a G to A substitution at nucleotide … (more)
The p.G52D variant (also known as c.155G>A), located in coding exon 2 of the ENG gene, results from a G to A substitution at nucleotide position 155. The glycine at codon 52 is replaced by aspartic acid, an amino acid with similar properties. This variant was observed in two newborns in two hereditary hemorrhagic telangiectasia (HHT) families, including one family presenting with pulmonary arteriovenous malformations (Paquet ME et al. Hum. Mol. Genet., 2001 Jun;10:1347-57; Letarte M et al. Cardiovasc. Res., 2005 Oct;68:155-64). Functional studies in one family revealed that this variant resulted in the accumulation of endoglin precursor with reduced levels of the mature protein compared ot wildtype. However, it is unknown if the newborn in this study is clinically affected with HHT and the affected adult relatives from this kinship were not tested (Paquet ME et al. Hum. Mol. Genet., 2001 Jun;10:1347-57). This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. Based on the majority of available evidence to date, this variant is likely to be pathogenic. (less)
Number of individuals with the variant: 1
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Likely pathogenic
(May 25, 2023)
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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: SCV003927539.1
First in ClinVar: Jun 03, 2023 Last updated: Jun 03, 2023 |
Comment:
Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; … (more)
Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 11440987, 32573726, 15907823) (less)
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Likely pathogenic
(Dec 16, 2022)
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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: SCV004295572.1
First in ClinVar: Feb 14, 2024 Last updated: Feb 14, 2024 |
Comment:
In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has … (more)
In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic. This variant disrupts the p.Gly52 amino acid residue in ENG. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 9554745, 15907823; Invitae). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. Studies have shown that this missense change alters ENG gene expression (PMID: 11440987). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is expected to disrupt ENG protein function. ClinVar contains an entry for this variant (Variation ID: 618085). This missense change has been observed in individual(s) with clinical features of hereditary hemorrhagic telangiectasia (PMID: 11440987). This variant is not present in population databases (gnomAD no frequency). This sequence change replaces glycine, which is neutral and non-polar, with aspartic acid, which is acidic and polar, at codon 52 of the ENG protein (p.Gly52Asp). (less)
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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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Mutational and phenotypic characterization of hereditary hemorrhagic telangiectasia. | Shovlin CL | Blood | 2020 | PMID: 32573726 |
Reduced endothelial secretion and plasma levels of transforming growth factor-beta1 in patients with hereditary hemorrhagic telangiectasia type 1. | Letarte M | Cardiovascular research | 2005 | PMID: 15907823 |
Analysis of several endoglin mutants reveals no endogenous mature or secreted protein capable of interfering with normal endoglin function. | Paquet ME | Human molecular genetics | 2001 | PMID: 11440987 |
Mutation and expression analysis of the endoglin gene in hereditary hemorrhagic telangiectasia reveals null alleles. | Gallione CJ | Human mutation | 1998 | PMID: 9554745 |
Text-mined citations for rs1564462765 ...
HelpRecord last updated Feb 20, 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.