VCV000002477.13 - ClinVar

NM_207122.2(EXT2):c.744-2A>C

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.

(4)

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_207122.2(EXT2):c.744-2A>C

Variation ID: 2477 Accession: VCV000002477.13

Type and length

single nucleotide variant, 1 bp

Location

Cytogenetic: 11p11.2 11: 44124787 (GRCh38) [ NCBI UCSC ] 11: 44146337 (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	Aug 22, 2016	Feb 14, 2024	Aug 4, 2023

HGVS

Nucleotide	Protein	Molecular consequence
NM_207122.2:c.744-2A>C MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.		splice acceptor
NM_000401.3:c.843-2A>C		splice acceptor
NM_001178083.3:c.744-2A>C		splice acceptor
NM_001389628.1:c.744-2A>C		splice acceptor
NM_001389630.1:c.744-2A>C		splice acceptor
NC_000011.10:g.44124787A>C
NC_000011.9:g.44146337A>C
NG_007560.1:g.34239A>C
LRG_494:g.34239A>C
LRG_494t1:c.843-2A>C
LRG_494t2:c.744-2A>C

... more HGVS ... less HGVS

Protein change

Other names

IVS4AS, A-C, -2

Canonical SPDI

NC_000011.10:44124786:A:C

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

exon loss; Variation Ontology [ VariO:0381] PubMed: 19344451

Global minor allele
frequency (GMAF)

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

The frequency of the allele represented by this VCV record.

Links

ClinGen: CA278579 OMIM: 608210.0007 dbSNP: rs864309638 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.
EXT2		Sufficient evidence for dosage pathogenicity	No evidence available	GRCh38 GRCh37	763	866

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.
Exostoses, multiple, type 2	Pathogenic (3)	criteria provided, multiple submitters, no conflicts	Apr 24, 2023	RCV000002581.15
EXT2-related disorder	Pathogenic (1)	criteria provided, single submitter	Aug 4, 2023	RCV003398422.4

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 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 (Apr 24, 2023)	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015)) Method: clinical testing	Exostoses, multiple, type 2 Affected status: unknown Allele origin: germline	Labcorp Genetics (formerly Invitae), Labcorp Accession: SCV000957980.6 First in ClinVar: Aug 14, 2019 Last updated: Feb 14, 2024	Publications: PubMed (4) PubMed: 19344451‚ 16199547‚ 10679937‚ 19810120 Comment: For these reasons, this variant has been classified as Pathogenic. Studies have shown that disruption of this splice site is associated with altered splicing resulting … (more) For these reasons, this variant has been classified as Pathogenic. Studies have shown that disruption of this splice site is associated with altered splicing resulting in multiple RNA products (PMID: 19344451). ClinVar contains an entry for this variant (Variation ID: 2477). Disruption of this splice site has been observed in individual(s) with hereditary multiple osteochondromatosis (PMID: 19344451; Invitae). This variant is not present in population databases (gnomAD no frequency). This sequence change affects an acceptor splice site in intron 4 of the EXT2 gene. It is expected to disrupt RNA splicing. Variants that disrupt the donor or acceptor splice site typically lead to a loss of protein function (PMID: 16199547), and loss-of-function variants in EXT2 are known to be pathogenic (PMID: 10679937, 19810120). (less)
Pathogenic (Mar 01, 2019)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Exostoses, multiple, type 2 (Autosomal dominant inheritance) Affected status: yes Allele origin: germline	Breda Genetics srl Accession: SCV001547507.1 First in ClinVar: Mar 28, 2021 Last updated: Mar 28, 2021	Comment: The variant c.843-2A>C in the EXT2 gene is reported as pathogenic for multiple exostoses type 2 in ClinVar (Variation ID: 2477). This variant has been … (more) The variant c.843-2A>C in the EXT2 gene is reported as pathogenic for multiple exostoses type 2 in ClinVar (Variation ID: 2477). This variant has been originally identified by Heinritz et al. (2009) in a male patient who was reported to have also an affected son. This nucleotide substitution results in two different skipping events: either only exon 5 or exons 5 and 6. Loss of exon 5 results in a frameshift with premature termination 18 amino acids downstream (p.Pro249Argfs*18), while loss of exons 5 and 6 leads to the in-frame deletion p.Pro249_Arg360del (PMID: 19344451). This variant has not been reported in gnomAD, 1000 Genomes, NHLI Exome Sequencing Project (ESP), or LOVD database v.3.0. (less)
Pathogenic (Aug 04, 2023)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	EXT2-related condition Affected status: unknown Allele origin: germline	PreventionGenetics, part of Exact Sciences Accession: SCV004104843.1 First in ClinVar: Nov 20, 2023 Last updated: Nov 20, 2023	Comment: The EXT2 c.744-2A>C variant is predicted to disrupt the AG splice acceptor site and interfere with normal splicing. This variant has been reported in an … (more) The EXT2 c.744-2A>C variant is predicted to disrupt the AG splice acceptor site and interfere with normal splicing. This variant has been reported in an individual with multiple osteochondromas (Heinritz et al. 2009. PubMed ID: 19344451). This variant has not been reported in a large population database (http://gnomad.broadinstitute.org), indicating this variant is rare. Variants that disrupt the consensus splice acceptor site in EXT2 are expected to be pathogenic. This variant is interpreted as pathogenic. (less)
Pathogenic (May 01, 2009)	no assertion criteria provided Method: literature only	EXOSTOSES, MULTIPLE, TYPE II Affected status: not provided Allele origin: germline	OMIM Accession: SCV000022739.5 First in ClinVar: Apr 04, 2013 Last updated: Aug 05, 2019	Publications: PubMed (1) PubMed: 19344451 Comment on evidence: In a German patient with multiple exostoses type II (EXT2; 133701), Heinritz et al. (2009) identified a heterozygous A-to-C transversion (744-2A-C) in a highly conserved … (more) In a German patient with multiple exostoses type II (EXT2; 133701), Heinritz et al. (2009) identified a heterozygous A-to-C transversion (744-2A-C) in a highly conserved nucleotide in intron 4 of the EXT2 gene. RT-PCR analysis identified 2 different splice variants skipping either only exon 5 or both exons 5 and 6. Loss of exon 5 results in a frameshift and premature termination, whereas loss of exons 5 and 6 leads to an in-frame deletion of 112 residues important for catalytic activity of the protein. (less)

Comment:

For these reasons, this variant has been classified as Pathogenic. Studies have shown that disruption of this splice site is associated with altered splicing resulting in multiple RNA products (PMID: 19344451). ClinVar contains an entry for this variant (Variation ID: 2477). Disruption of this splice site has been observed in individual(s) with hereditary multiple osteochondromatosis (PMID: 19344451; Invitae). This variant is not present in population databases (gnomAD no frequency). This sequence change affects an acceptor splice site in intron 4 of the EXT2 gene. It is expected to disrupt RNA splicing. Variants that disrupt the donor or acceptor splice site typically lead to a loss of protein function (PMID: 16199547), and loss-of-function variants in EXT2 are known to be pathogenic (PMID: 10679937, 19810120).

Comment:

The variant c.843-2A>C in the EXT2 gene is reported as pathogenic for multiple exostoses type 2 in ClinVar (Variation ID: 2477). This variant has been originally identified by Heinritz et al. (2009) in a male patient who was reported to have also an affected son. This nucleotide substitution results in two different skipping events: either only exon 5 or exons 5 and 6. Loss of exon 5 results in a frameshift with premature termination 18 amino acids downstream (p.Pro249Argfs*18), while loss of exons 5 and 6 leads to the in-frame deletion p.Pro249_Arg360del (PMID: 19344451). This variant has not been reported in gnomAD, 1000 Genomes, NHLI Exome Sequencing Project (ESP), or LOVD database v.3.0.

Comment:

The EXT2 c.744-2A>C variant is predicted to disrupt the AG splice acceptor site and interfere with normal splicing. This variant has been reported in an individual with multiple osteochondromas (Heinritz et al. 2009. PubMed ID: 19344451). This variant has not been reported in a large population database (http://gnomad.broadinstitute.org), indicating this variant is rare. Variants that disrupt the consensus splice acceptor site in EXT2 are expected to be pathogenic. This variant is interpreted 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
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
Splicing in action: assessing disease causing sequence changes.	Baralle D	Journal of medical genetics	2005	PMID: 16199547
Molecular basis of multiple exostoses: mutations in the EXT1 and EXT2 genes.	Wuyts W	Human mutation	2000	PMID: 10679937

Text-mined citations for rs864309638 ...

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_207122.2(EXT2):c.744-2A>C

Variant Details

Genes

Conditions - Germline

Submissions - Germline

Germline Functional Evidence

Citations for germline classification of this variant

Text-mined citations for rs864309638 ...