ClinVar Genomic variation as it relates to human health
NM_000127.3(EXT1):c.1019G>A (p.Arg340His)
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_000127.3(EXT1):c.1019G>A (p.Arg340His)
Variation ID: 265129 Accession: VCV000265129.14
- Type and length
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single nucleotide variant, 1 bp
- Location
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Cytogenetic: 8q24.11 8: 117837145 (GRCh38) [ NCBI UCSC ] 8: 118849384 (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 Oct 10, 2016 Feb 14, 2024 Dec 18, 2023 - HGVS
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Nucleotide Protein Molecular
consequenceNM_000127.3:c.1019G>A MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_000118.2:p.Arg340His missense NC_000008.11:g.117837145C>T NC_000008.10:g.118849384C>T NG_007455.2:g.279675G>A LRG_493:g.279675G>A LRG_493t1:c.1019G>A LRG_493p1:p.Arg340His Q16394:p.Arg340His - Protein change
- R340H
- Other names
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- Canonical SPDI
- NC_000008.11:117837144: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.
The Genome Aggregation Database (gnomAD), exomes 0.00000
Exome Aggregation Consortium (ExAC) 0.00001
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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EXT1 | Sufficient evidence for dosage pathogenicity | No evidence available |
GRCh38 GRCh37 |
958 | 1029 |
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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Pathogenic (2) |
criteria provided, multiple submitters, no conflicts
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Oct 27, 2021 | RCV000254839.4 | |
Pathogenic (2) |
criteria provided, single submitter
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Dec 18, 2023 | RCV000630812.10 | |
Pathogenic (2) |
criteria provided, single submitter
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May 22, 2022 | RCV001263553.3 |
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
(May 22, 2022)
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criteria provided, single submitter
Method: clinical testing
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Exostoses, multiple, type 1
Affected status: yes
Allele origin:
germline
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3billion
Accession: SCV002521833.1
First in ClinVar: Jun 03, 2022 Last updated: Jun 03, 2022 |
Comment:
The variant is observed at an extremely low frequency in the gnomAD v2.1.1 dataset (total allele frequency: <0.001%). Protein truncation variants are a common disease-causing … (more)
The variant is observed at an extremely low frequency in the gnomAD v2.1.1 dataset (total allele frequency: <0.001%). Protein truncation variants are a common disease-causing mechanism. In silico tool predictions suggest damaging effect of the variant on gene or gene product (REVEL: 0.84; 3Cnet: 0.78). Same nucleotide change resulting in same amino acid change has been previously reported as pathogenic/likely pathogenic with strong evidence (ClinVar ID: VCV000265129). The variant has been observed in multiple (>3) similarly affected unrelated individuals (PMID:19810120). Different missense changes at the same codon (p.Arg340Cys, p.Arg340Gly, p.Arg340Leu) have been reported as pathogenic/likely pathogenic with strong evidence (ClinVar ID: VCV000002495, VCV000002500, VCV000988576). Therefore, this variant is classified as pathogenic according to the recommendation of ACMG/AMP guideline. (less)
Clinical Features:
Cerebellar atrophy (present) , Elevated circulating alpha-fetoprotein concentration (present) , Enlarged cisterna magna (present) , Abnormal cerebellum morphology (present) , Nystagmus (present) , Preaxial hand … (more)
Cerebellar atrophy (present) , Elevated circulating alpha-fetoprotein concentration (present) , Enlarged cisterna magna (present) , Abnormal cerebellum morphology (present) , Nystagmus (present) , Preaxial hand polydactyly (present) , Hand polydactyly (present) , Intellectual disability, mild (present) , Exostoses (present) , Telangiectasia (present) , Gait ataxia (present) (less)
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Pathogenic
(Oct 27, 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: SCV000321613.9
First in ClinVar: Oct 10, 2016 Last updated: Mar 04, 2023 |
Comment:
Not observed at a significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant has a deleterious effect on protein … (more)
Not observed at a 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: 11391482, 10713884, 26239617, 24532482, 19810120, 23439489, 9521425, 11170095, 26961984, 25468659, 33414810, 30334991, 30806661, 34006472, 33552269) (less)
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Pathogenic
(Jun 22, 2021)
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criteria provided, single submitter
Method: clinical testing
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not provided
Affected status: not provided
Allele origin:
germline
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Institute for Clinical Genetics, University Hospital TU Dresden, University Hospital TU Dresden
Accession: SCV004026144.1
First in ClinVar: Aug 19, 2023 Last updated: Aug 19, 2023 |
Comment:
PP4, PP5, PS4, PM2_SUP, PP1
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Pathogenic
(Dec 18, 2023)
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criteria provided, single submitter
Method: clinical testing
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Multiple congenital exostosis
Affected status: unknown
Allele origin:
germline
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Invitae
Accession: SCV000751779.8
First in ClinVar: May 28, 2018 Last updated: Feb 14, 2024 |
Comment:
This sequence change replaces arginine, which is basic and polar, with histidine, which is basic and polar, at codon 340 of the EXT1 protein (p.Arg340His). … (more)
This sequence change replaces arginine, which is basic and polar, with histidine, which is basic and polar, at codon 340 of the EXT1 protein (p.Arg340His). This variant is present in population databases (rs119103287, gnomAD 0.0009%). This missense change has been observed in individual(s) with hereditary multiple osteochondromas, also known as hereditary multiple exostoses (PMID: 9521425, 10713884, 19810120, 23439489, 24532482, 25468659, 26239617, 26961984). In at least one individual the variant was observed to be de novo. It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 265129). 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) has been performed at Invitae for this missense variant, however the output from this modeling did not meet the statistical confidence thresholds required to predict the impact of this variant on EXT1 protein function. Experimental studies have shown that this missense change affects EXT1 function (PMID: 11391482). For these reasons, this variant has been classified as Pathogenic. (less)
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Pathogenic
(Nov 06, 2020)
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no assertion criteria provided
Method: literature only
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EXOSTOSES, MULTIPLE, TYPE I
Affected status: not provided
Allele origin:
germline
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OMIM
Accession: SCV001441614.1
First in ClinVar: Nov 12, 2020 Last updated: Nov 12, 2020 |
Comment on evidence:
In 5 unrelated Italian patients with multiple exostoses type I (EXT1; 133700), Fusco et al. (2019) identified a heterozygous c.1019G-A transition (c.1019G-A, NM_000127.2) in exon … (more)
In 5 unrelated Italian patients with multiple exostoses type I (EXT1; 133700), Fusco et al. (2019) identified a heterozygous c.1019G-A transition (c.1019G-A, NM_000127.2) in exon 2 of the EXT1 gene, resulting in an arg340-to-his (R340H) substitution. The mutation was identified by direct sequencing of the EXT1 gene. Functional studies were not performed. (less)
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Pathogenic
(May 31, 2019)
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no assertion criteria provided
Method: research
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Exostoses, multiple, type 1
Affected status: yes
Allele origin:
paternal
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Beijing Key Laboratory for Genetic Research of Skeletal Deformity, Peking Union Medical College Hospital
Accession: SCV001482330.1
First in ClinVar: Mar 07, 2021 Last updated: Mar 07, 2021 |
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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 spectrum and clinical signatures in 114 families with hereditary multiple osteochondromas: insights into molecular properties of selected exostosin variants. | Fusco C | Human molecular genetics | 2019 | PMID: 30806661 |
Large-scale mutational analysis in the EXT1 and EXT2 genes for Japanese patients with multiple osteochondromas. | Ishimaru D | BMC genetics | 2016 | PMID: 26961984 |
Hereditary multiple exostoses and solitary osteochondroma associated with growth hormone deficiency: to treat or not to treat? | Bozzola M | Italian journal of pediatrics | 2015 | PMID: 26239617 |
Loss of function in heparan sulfate elongation genes EXT1 and EXT 2 results in improved nitric oxide bioavailability and endothelial function. | Mooij HL | Journal of the American Heart Association | 2014 | PMID: 25468659 |
Mutational screening of EXT1 and EXT2 genes in Polish patients with hereditary multiple exostoses. | Jamsheer A | Journal of applied genetics | 2014 | PMID: 24532482 |
Mutations in the EXT1 and EXT2 genes in Spanish patients with multiple osteochondromas. | Sarrión P | Scientific reports | 2013 | PMID: 23439489 |
Multiple osteochondromas: mutation update and description of the multiple osteochondromas mutation database (MOdb). | Jennes I | Human mutation | 2009 | PMID: 19810120 |
Etiological point mutations in the hereditary multiple exostoses gene EXT1: a functional analysis of heparan sulfate polymerase activity. | Cheung PK | American journal of human genetics | 2001 | PMID: 11391482 |
Comparison of fluorescent single-strand conformation polymorphism analysis and denaturing high-performance liquid chromatography for detection of EXT1 and EXT2 mutations in hereditary multiple exostoses. | Dobson-Stone C | European journal of human genetics : EJHG | 2000 | PMID: 10713884 |
Evaluation of locus heterogeneity and EXT1 mutations in 34 families with hereditary multiple exostoses. | Raskind WH | Human mutation | 1998 | PMID: 9521425 |
Text-mined citations for rs119103287 ...
HelpRecord last updated Mar 30, 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.