VCV000265131.22 - ClinVar

NM_000127.3(EXT1):c.1469del (p.Leu490fs)

Germline

Classification

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.

(10)

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

criteria provided, multiple submitters, no conflicts

Somatic

No data submitted for somatic clinical impact

Somatic

No data submitted for oncogenicity

Variant Details

Identifiers

NM_000127.3(EXT1):c.1469del (p.Leu490fs)

Variation ID: 265131 Accession: VCV000265131.22

Type and length

Deletion, 1 bp

Location

Cytogenetic: 8q24.11 8: 117819743 (GRCh38) [ NCBI UCSC ] 8: 118831982 (GRCh37) [ NCBI UCSC ]

Timeline in ClinVar

	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	Dec 19, 2017	Aug 4, 2024	Jul 30, 2024

HGVS

Nucleotide	Protein	Molecular consequence
NM_000127.3:c.1469del MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.	NP_000118.2:p.Leu490fs	frameshift
NM_000127.2:c.1469delT		frameshift
NC_000008.11:g.117819743del
NC_000008.10:g.118831982del
NG_007455.2:g.297077del
LRG_493:g.297077del
LRG_493t1:c.1469del	LRG_493p1:p.Leu490fs

... more HGVS ... less HGVS

Protein change

L490fs

Other names

Canonical SPDI

NC_000008.11:117819742:A:

Functional consequence Help The effect of the variant on RNA or protein function, based on experimental evidence from submitters.

Global minor allele frequency (GMAF) Help The 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.

Allele frequency Help The frequency of the allele represented by this VCV record.

Links

ClinGen: CA10588447 OMIM: 608177.0001 dbSNP: rs886039356 VarSome

Genes

Gene	OMIM	ClinGen Gene Dosage Sensitivity Curation		Variation Viewer Help Links to Variation Viewer, a genome browser to view variation data from NCBI databases.	Related variants
Gene	OMIM	HI score Help The haploinsufficiency score for the gene, curated by ClinGen’s Dosage Sensitivity Curation task team.	TS score Help The triplosensitivity score for the gene, curated by ClinGen’s Dosage Sensitivity Curation task team.		Within gene Help The number of variants in ClinVar that are contained within this gene, with a link to view the list of variants.	All Help 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.
EXT1		Sufficient evidence for dosage pathogenicity	No evidence available	GRCh38 GRCh37	999	1074

Conditions - Germline

Condition Help 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 Help The most recent date that a submitter evaluated this variant for the condition.	Variation/condition record Help The RCV accession number, with most recent version number, for the variant-condition record, with a link to the RCV web page.
not provided	Pathogenic (1)	criteria provided, single submitter	Nov 17, 2021	RCV000255784.5
Exostoses, multiple, type 1	Pathogenic (7)	criteria provided, multiple submitters, no conflicts	Jul 30, 2024	RCV001003498.10
Multiple congenital exostosis	Pathogenic (1)	criteria provided, single submitter	Feb 22, 2023	RCV000702125.10
Chondrosarcoma	Pathogenic (1)	criteria provided, single submitter	Dec 12, 2023	RCV004567807.1

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 Help 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 Help 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.
Pathogenic (Nov 17, 2021)	criteria provided, single submitter (GeneDx Variant Classification Process June 2021) Method: clinical testing	Not Provided Affected status: yes Allele origin: germline	GeneDx Accession: SCV000321615.9 First in ClinVar: Oct 10, 2016 Last updated: Mar 04, 2023	Comment: Frameshift 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; Not … (more) Frameshift 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; Not observed in large population cohorts (Lek et al., 2016); This variant is associated with the following publications: (PMID: 23439489, 10679937, 29529714, 23262345, 18165274, 16088908, 9326317, 11432960, 17301954, 9150727, 9463333, 10480354, 7550340, 21039224, 29126381, 19810120, 11391482, 30334991, 30806661, 33632255, 32293802, 33552269) (less)
Pathogenic (Mar 24, 2022)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Exostoses, multiple, type 1 Affected status: yes Allele origin: germline	Laboratory of Medical Genetics, National & Kapodistrian University of Athens Accession: SCV002577583.1 First in ClinVar: Oct 08, 2022 Last updated: Oct 08, 2022	Comment: PVS1, PM2, PP3, PP5
Pathogenic (Dec 14, 2022)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Exostoses, multiple, type 1 Affected status: yes Allele origin: germline	Greenwood Genetic Center Diagnostic Laboratories, Greenwood Genetic Center Accession: SCV003799045.2 First in ClinVar: Feb 13, 2023 Last updated: Mar 04, 2023	Comment: PVS1, PS4, PM2, PM6
Pathogenic (-)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: not provided	Exostoses, multiple, type 1 (Autosomal dominant inheritance) Affected status: yes Allele origin: germline	Institute of Human Genetics, University Hospital of Duesseldorf Accession: SCV004046799.1 First in ClinVar: Oct 21, 2023 Last updated: Oct 21, 2023
Pathogenic (Feb 22, 2023)	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015)) Method: clinical testing	Multiple congenital exostosis Affected status: unknown Allele origin: germline	Labcorp Genetics (formerly Invitae), Labcorp Accession: SCV000830961.7 First in ClinVar: Oct 10, 2018 Last updated: Feb 14, 2024	Publications: PubMed (7) PubMed: 28492532‚ 7550340‚ 23439489‚ 29126381‚ 10679937‚ 11391482‚ 19810120 Comment: For these reasons, this variant has been classified as Pathogenic. ClinVar contains an entry for this variant (Variation ID: 265131). This premature translational stop signal … (more) For these reasons, this variant has been classified as Pathogenic. ClinVar contains an entry for this variant (Variation ID: 265131). This premature translational stop signal has been observed in individuals with multiple osteochondromas and hereditary multiple osteochondromas (PMID: 7550340, 23439489, 29126381). It has also been observed to segregate with disease in related individuals. This variant is not present in population databases (gnomAD no frequency). This sequence change creates a premature translational stop signal (p.Leu490Argfs*9) in the EXT1 gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in EXT1 are known to be pathogenic (PMID: 10679937, 11391482, 19810120). (less)
Pathogenic (Dec 12, 2023)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Chondrosarcoma Affected status: unknown Allele origin: unknown	Baylor Genetics Accession: SCV005060409.1 First in ClinVar: Jun 17, 2024 Last updated: Jun 17, 2024
Pathogenic (-)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Exostoses, multiple, type 1 (Autosomal dominant inheritance) Affected status: yes Allele origin: germline	Neuberg Centre For Genomic Medicine, NCGM Accession: SCV005073943.1 First in ClinVar: Jul 15, 2024 Last updated: Jul 15, 2024	Comment: The observed frameshift variant c.1469del (p.Leu490ArgfsTer9) in EXT1 gene has been reported in heterozygous state in multiple individuals affected with Exostoses (Kim S et al. … (more) The observed frameshift variant c.1469del (p.Leu490ArgfsTer9) in EXT1 gene has been reported in heterozygous state in multiple individuals affected with Exostoses (Kim S et al. 2022; Mohaidat Z et al. 2021; Santos SCL et al. 2018). The p.Leu490ArgfsTer9 variant is absent in gnomAD Exomes. This variant has been submitted to the ClinVar database as Pathogenic (multiple submitters). This variant causes a frameshift starting with codon Leucine 490, changes this amino acid to Arginine residue, and creates a premature Stop codon at position 9 of the new reading frame, denoted p.Leu490ArgfsTer9. This variant is predicted to cause loss of normal protein function through protein truncation. Loss-of-function variants in EXT1 are known to be pathogenic (Jennes I et al. 2009). For these reasons, this variant has been classified as Pathogenic (less) Clinical Features: Abnormality of the skeletal system (present)
Pathogenic (Jul 30, 2024)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Exostoses, multiple, type 1 Affected status: yes Allele origin: germline	Department of Human Genetics, Hannover Medical School Accession: SCV005088712.1 First in ClinVar: Aug 04, 2024 Last updated: Aug 04, 2024	Clinical Features: Multiple congenital exostosis (present)
Pathogenic (Oct 01, 1995)	no assertion criteria provided Method: literature only	EXOSTOSES, MULTIPLE, TYPE I Affected status: not provided Allele origin: germline	OMIM Accession: SCV000022756.2 First in ClinVar: Apr 04, 2013 Last updated: May 02, 2019	Publications: PubMed (1) PubMed: 7550340 Comment on evidence: In 2 of 23 unrelated families with multiple exostoses type I (EXT1; 133700), Ahn et al. (1995) identified a 1-bp deletion (2120T) in the EXT1 … (more) In 2 of 23 unrelated families with multiple exostoses type I (EXT1; 133700), Ahn et al. (1995) identified a 1-bp deletion (2120T) in the EXT1 gene, resulting in a premature stop codon. The mutation cosegregated with the disease in the families over 2 and 3 generations, respectively. (less)
Pathogenic (Sep 26, 2019)	no assertion criteria provided Method: clinical testing	Exostoses, multiple, type 1 Affected status: yes Allele origin: germline	Biochemical Molecular Genetic Laboratory, King Abdulaziz Medical City Accession: SCV001133029.1 First in ClinVar: Jan 06, 2020 Last updated: Jan 06, 2020

Comment:

Frameshift 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; Not observed in large population cohorts (Lek et al., 2016); This variant is associated with the following publications: (PMID: 23439489, 10679937, 29529714, 23262345, 18165274, 16088908, 9326317, 11432960, 17301954, 9150727, 9463333, 10480354, 7550340, 21039224, 29126381, 19810120, 11391482, 30334991, 30806661, 33632255, 32293802, 33552269)

Comment:

For these reasons, this variant has been classified as Pathogenic. ClinVar contains an entry for this variant (Variation ID: 265131). This premature translational stop signal has been observed in individuals with multiple osteochondromas and hereditary multiple osteochondromas (PMID: 7550340, 23439489, 29126381). It has also been observed to segregate with disease in related individuals. This variant is not present in population databases (gnomAD no frequency). This sequence change creates a premature translational stop signal (p.Leu490Argfs*9) in the EXT1 gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in EXT1 are known to be pathogenic (PMID: 10679937, 11391482, 19810120).

Comment:

The observed frameshift variant c.1469del (p.Leu490ArgfsTer9) in EXT1 gene has been reported in heterozygous state in multiple individuals affected with Exostoses (Kim S et al. 2022; Mohaidat Z et al. 2021; Santos SCL et al. 2018). The p.Leu490ArgfsTer9 variant is absent in gnomAD Exomes. This variant has been submitted to the ClinVar database as Pathogenic (multiple submitters). This variant causes a frameshift starting with codon Leucine 490, changes this amino acid to Arginine residue, and creates a premature Stop codon at position 9 of the new reading frame, denoted p.Leu490ArgfsTer9. This variant is predicted to cause loss of normal protein function through protein truncation. Loss-of-function variants in EXT1 are known to be pathogenic (Jennes I et al. 2009). For these reasons, this variant has been classified as Pathogenic

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.

Comment:

Citations for germline classification of this variant

Title	Author	Journal	Year	Link
A genotype-phenotype study of hereditary multiple exostoses in forty-six Chinese patients.	Li Y	BMC medical genetics	2017	PMID: 29126381
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
Molecular basis of multiple exostoses: mutations in the EXT1 and EXT2 genes.	Wuyts W	Human mutation	2000	PMID: 10679937
Cloning of the putative tumour suppressor gene for hereditary multiple exostoses (EXT1).	Ahn J	Nature genetics	1995	PMID: 7550340

Text-mined citations for rs886039356 ...

These citations are identified by LitVar using the rs number, so they may include citations for more than one variant at this location. Please review the LitVar results carefully for your variant of interest.

Record last updated Sep 29, 2024

ClinVar Genomic variation as it relates to human health

NM_000127.3(EXT1):c.1469del (p.Leu490fs)

Variant Details

Genes

Conditions - Germline

Submissions - Germline

Germline Functional Evidence

Citations for germline classification of this variant

Text-mined citations for rs886039356 ...