ClinVar Genomic variation as it relates to human health
NM_001114753.3(ENG):c.899T>C (p.Leu300Pro)
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.899T>C (p.Leu300Pro)
Variation ID: 618623 Accession: VCV000618623.16
- Type and length
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single nucleotide variant, 1 bp
- Location
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Cytogenetic: 9q34.11 9: 130587171 (GRCh37) [ NCBI UCSC ] 9: 127824892 (GRCh38) [ 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 Nov 2, 2023 - HGVS
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Nucleotide Protein Molecular
consequenceNM_001114753.3:c.899T>C MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_001108225.1:p.Leu300Pro missense NM_000118.4:c.899T>C NP_000109.1:p.Leu300Pro missense NM_001278138.2:c.353T>C NP_001265067.1:p.Leu118Pro missense NM_001406715.1:c.899T>C NP_001393644.1:p.Leu300Pro missense NC_000009.12:g.127824892A>G NC_000009.11:g.130587171A>G NG_009551.1:g.34877T>C LRG_589:g.34877T>C LRG_589t1:c.899T>C LRG_589p1:p.Leu300Pro LRG_589t2:c.899T>C LRG_589p2:p.Leu300Pro - Protein change
- L300P, L118P
- Other names
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- Canonical SPDI
- NC_000009.12:127824891:A:G
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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.
Trans-Omics for Precision Medicine (TOPMed) 0.00001
- 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 |
1075 | 1576 |
Conditions - Germline
Condition
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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
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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 (3) |
criteria provided, multiple submitters, no conflicts
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Aug 31, 2023 | RCV000757215.13 | |
Likely pathogenic (1) |
criteria provided, single submitter
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Jan 1, 2018 | RCV001263078.3 | |
Likely pathogenic (1) |
criteria provided, single submitter
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Nov 10, 2022 | RCV002370008.2 | |
Pathogenic (1) |
criteria provided, single submitter
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Nov 2, 2023 | RCV003594026.1 |
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
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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
(Sep 22, 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: SCV000885359.1
First in ClinVar: Feb 18, 2019 Last updated: Feb 18, 2019 |
Comment:
The ENG c.899T>C, p.Leu300Pro variant has been reported in a family affected with hereditary hemorrhagic telangiectasia (Gedge 2007), segregating with the disease in multiple family … (more)
The ENG c.899T>C, p.Leu300Pro variant has been reported in a family affected with hereditary hemorrhagic telangiectasia (Gedge 2007), segregating with the disease in multiple family members (Bayrak-Toydemir 2008). It is not observed in the general population databases, such as the 1000 Genomes Project, the Exome Variant Server, or the Genome Aggregation Database. The leucine at residue 300 is moderately conserved, and computational algorithms (Align GV/GD, PolyPhen-2, SIFT) predict that the variant has an impact on the protein. Based on the above information, the variant is classified as pathogenic. REFERENCES Bayrak-Toydemir P et al. Likelihood ratios to assess genetic evidence for clinical significance of uncertain variants: hereditary hemorrhagic telangiectasia as a model. Exp Mol Pathol. 2008 Aug;85(1):45-9. Gedge F et al. Clinical and analytical sensitivities in hereditary hemorrhagic telangiectasia testing and a report of de novo mutations. J Mol Diagn. 2007 Apr;9(2):258-65. (less)
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Likely pathogenic
(Feb 22, 2023)
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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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Mayo Clinic Laboratories, Mayo Clinic
Accession: SCV004226813.1
First in ClinVar: Jan 06, 2024 Last updated: Jan 06, 2024 |
Comment:
PP1_strong, PM2_supporting, PS4_moderate
Number of individuals with the variant: 1
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Pathogenic
(Nov 02, 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: SCV004294040.1
First in ClinVar: Feb 14, 2024 Last updated: Feb 14, 2024 |
Comment:
This sequence change replaces leucine, which is neutral and non-polar, with proline, which is neutral and non-polar, at codon 300 of the ENG protein (p.Leu300Pro). … (more)
This sequence change replaces leucine, which is neutral and non-polar, with proline, which is neutral and non-polar, at codon 300 of the ENG protein (p.Leu300Pro). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with hereditary hemorrhagic telangiectasia (PMID: 17384219, 18495117, 32573726). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 618623). 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 with a positive predictive value of 80%. For these reasons, this variant has been classified as Pathogenic. (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: SCV001441158.1
First in ClinVar: Oct 31, 2020 Last updated: Oct 31, 2020 |
Comment:
PM2+PM1+PP4+PP5
Number of individuals with the variant: 1
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Likely pathogenic
(Nov 10, 2022)
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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: SCV002683835.2
First in ClinVar: Nov 29, 2022 Last updated: Apr 15, 2023 |
Comment:
The p.L300P variant (also known as c.899T>C), located in coding exon 7 of the ENG gene, results from a T to C substitution at nucleotide … (more)
The p.L300P variant (also known as c.899T>C), located in coding exon 7 of the ENG gene, results from a T to C substitution at nucleotide position 899. The leucine at codon 300 is replaced by proline, an amino acid with similar properties. This variant has been reported in multiple affected individuals from a family with hereditary hemorrhagic telangiectasia (HHT) (Bayrak-Toydemir P, Exp. Mol. Pathol. 2008 Aug; 85(1):45-9). This variant was also detected in HHT cohorts and in additional individuals with features consistent with HHT (Gedge F et al. J Mol Diagn, 2007 Apr;9:258-65; Shovlin CL et al. Blood. 2020 10;136(17):1907-1918; Ambry internal data). This variant is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). Based on internal structural analysis, this variant is moderately disruptive to the structure of the ENG OR1 domain, to a higher degree than nearby pathogenic variants (Nolan-Stevaux O et al. PLoS ONE, 2012 Dec;7:e50920; Saito T et al. Cell Rep, 2017 05;19:1917-1928). This amino acid position is not well 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)
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Likely pathogenic
(Aug 31, 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: SCV002525338.3
First in ClinVar: Jun 11, 2022 Last updated: Sep 14, 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: 32573726, 17384219, 18495117) (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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Gene Mutation Annotation and Pedigree for Pulmonary Arterial Hypertension Patients in Han Chinese Patients. | Wang MT | Global heart | 2021 | PMID: 34900561 |
Mutational and phenotypic characterization of hereditary hemorrhagic telangiectasia. | Shovlin CL | Blood | 2020 | PMID: 32573726 |
Structural Basis of the Human Endoglin-BMP9 Interaction: Insights into BMP Signaling and HHT1. | Saito T | Cell reports | 2017 | PMID: 28564608 |
Endoglin requirement for BMP9 signaling in endothelial cells reveals new mechanism of action for selective anti-endoglin antibodies. | Nolan-Stevaux O | PloS one | 2012 | PMID: 23300529 |
Likelihood ratios to assess genetic evidence for clinical significance of uncertain variants: hereditary hemorrhagic telangiectasia as a model. | Bayrak-Toydemir P | Experimental and molecular pathology | 2008 | PMID: 18495117 |
Clinical and analytical sensitivities in hereditary hemorrhagic telangiectasia testing and a report of de novo mutations. | Gedge F | The Journal of molecular diagnostics : JMD | 2007 | PMID: 17384219 |
Text-mined citations for rs1335718486 ...
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.