ClinVar Genomic variation as it relates to human health
NM_207122.2(EXT2):c.1945C>T (p.Arg649Ter)
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.
Pathogenic(2); Likely pathogenic(4); Uncertain significance(1)
No data submitted for somatic clinical impact
No data submitted for oncogenicity
Variant Details
- Identifiers
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NM_207122.2(EXT2):c.1945C>T (p.Arg649Ter)
Variation ID: 838313 Accession: VCV000838313.39
- Type and length
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single nucleotide variant, 1 bp
- Location
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Cytogenetic: 11p11.2 11: 44236302 (GRCh38) [ NCBI UCSC ] 11: 44257852 (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 Apr 15, 2020 May 12, 2024 Jan 18, 2024 - HGVS
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Nucleotide Protein Molecular
consequenceNM_207122.2:c.1945C>T MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_997005.1:p.Arg649Ter nonsense NM_000401.3:c.2044C>T NP_000392.3:p.Arg682Ter nonsense NM_001178083.3:c.1975C>T NP_001171554.1:p.Arg659Ter nonsense NM_001389628.1:c.1945C>T NP_001376557.1:p.Arg649Ter nonsense NM_001389630.1:c.1945C>T NP_001376559.1:p.Arg649Ter nonsense NC_000011.10:g.44236302C>T NC_000011.9:g.44257852C>T NG_007560.1:g.145754C>T LRG_494:g.145754C>T LRG_494t1:c.2044C>T LRG_494p1:p.Arg682Ter LRG_494t2:c.1945C>T - Protein change
- R682*, R649*, R659*
- Other names
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- Canonical SPDI
- NC_000011.10:44236301: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.
Trans-Omics for Precision Medicine (TOPMed) 0.00003
The Genome Aggregation Database (gnomAD) 0.00004
Exome Aggregation Consortium (ExAC) 0.00005
The Genome Aggregation Database (gnomAD), exomes 0.00004
- 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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EXT2 | Sufficient evidence for dosage pathogenicity | No evidence available |
GRCh38 GRCh37 |
731 | 829 |
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
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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Conflicting interpretations of pathogenicity (4) |
criteria provided, conflicting classifications
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Jan 18, 2024 | RCV001039837.16 | |
Likely pathogenic (2) |
criteria provided, multiple submitters, no conflicts
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Aug 1, 2022 | RCV001091959.19 | |
Likely pathogenic (1) |
criteria provided, single submitter
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Jan 11, 2022 | RCV002221603.4 |
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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Uncertain significance
(Jul 26, 2018)
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criteria provided, single submitter
Method: clinical testing
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Exostoses, multiple, type 2
Affected status: unknown
Allele origin:
germline
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Illumina Laboratory Services, Illumina
Accession: SCV001259402.1
First in ClinVar: May 31, 2020 Last updated: May 31, 2020 |
Comment:
This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, … (more)
This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). Publications were found based on this search. However, the evidence from the literature, in combination with allele frequency data from public databases where available, was not sufficient to rule this variant in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance. (less)
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Likely pathogenic
(Jan 11, 2022)
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criteria provided, single submitter
Method: clinical testing
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Exostoses, multiple, type 2
Seizures-scoliosis-macrocephaly syndrome
Affected status: yes
Allele origin:
germline
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Greenwood Genetic Center Diagnostic Laboratories, Greenwood Genetic Center
Accession: SCV002499171.1
First in ClinVar: Apr 16, 2022 Last updated: Apr 16, 2022 |
Comment:
PVS1, PM2, PS4_Supporiting
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Likely pathogenic
(Dec 29, 2021)
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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: SCV001763799.3
First in ClinVar: Aug 07, 2021 Last updated: Mar 04, 2023 |
Comment:
Nonsense variant predicted to result in protein truncation or nonsense mediated decay in a gene for which loss-of-function is a known mechanism of disease; This … (more)
Nonsense variant predicted to result in protein truncation or nonsense mediated decay in a gene for which loss-of-function is a known mechanism of disease; This variant is associated with the following publications: (PMID: 29625052, 25525159, 19344451, 26689913) (less)
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Likely pathogenic
(May 31, 2023)
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criteria provided, single submitter
Method: clinical testing
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Exostoses, multiple, type 2
Affected status: unknown
Allele origin:
germline
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St. Jude Molecular Pathology, St. Jude Children's Research Hospital
Accession: SCV004031175.1
First in ClinVar: Sep 03, 2023 Last updated: Sep 03, 2023 |
Comment:
The EXT2 c.2044C>T (p.Arg682Ter) change is a nonsense variant that is predicted to cause premature protein truncation or absence of protein due to nonsense-mediated decay. … (more)
The EXT2 c.2044C>T (p.Arg682Ter) change is a nonsense variant that is predicted to cause premature protein truncation or absence of protein due to nonsense-mediated decay. This variant has been reported in an individual with multiple osteochondromas (PMID: 19344451). This variant has a maximum subpopulation frequency of 0.006% in gnomAD v2.1.1. This variant corresponds to NM_207122.1:c.1945C>T (p.Arg649Ter) in the MANE select transcript. In summary, this variant meets criteria to be classified as likely pathogenic.? (less)
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Pathogenic
(Oct 22, 2023)
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criteria provided, single submitter
Method: clinical testing
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Exostoses, multiple, type 2
Affected status: unknown
Allele origin:
unknown
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Baylor Genetics
Accession: SCV004192785.1
First in ClinVar: Dec 30, 2023 Last updated: Dec 30, 2023 |
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Pathogenic
(Jan 18, 2024)
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criteria provided, single submitter
Method: clinical testing
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Exostoses, multiple, type 2
Affected status: unknown
Allele origin:
germline
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Invitae
Accession: SCV001203386.5
First in ClinVar: Apr 15, 2020 Last updated: Feb 14, 2024 |
Comment:
This sequence change creates a premature translational stop signal (p.Arg649*) in the EXT2 gene. It is expected to result in an absent or disrupted protein … (more)
This sequence change creates a premature translational stop signal (p.Arg649*) in the EXT2 gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in EXT2 are known to be pathogenic (PMID: 10679937, 19810120). This variant is present in population databases (rs765648513, gnomAD 0.007%). This premature translational stop signal has been observed in individual(s) with multiple osteochondromas (PMID: 19344451). ClinVar contains an entry for this variant (Variation ID: 838313). For these reasons, this variant has been classified as Pathogenic. (less)
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Likely pathogenic
(Aug 01, 2022)
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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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CeGaT Center for Human Genetics Tuebingen
Accession: SCV001248263.21
First in ClinVar: May 12, 2020 Last updated: May 12, 2024 |
Comment:
EXT2: PVS1, PS4:Supporting
Number of individuals with the variant: 2
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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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Multiple osteochondromas: mutation update and description of the multiple osteochondromas mutation database (MOdb). | Jennes I | Human mutation | 2009 | PMID: 19810120 |
New mutations of EXT1 and EXT2 genes in German patients with Multiple Osteochondromas. | Heinritz W | Annals of human genetics | 2009 | PMID: 19344451 |
Molecular basis of multiple exostoses: mutations in the EXT1 and EXT2 genes. | Wuyts W | Human mutation | 2000 | PMID: 10679937 |
Text-mined citations for rs765648513 ...
HelpRecord last updated May 12, 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.