NM_207122.2(EXT2):c.744-2A>C AND Exostoses, multiple, type 2

Germline classification:: Pathogenic (3 submissions)
Last evaluated:: Apr 24, 2023
Review status:: 2 stars out of maximum of 4 stars
criteria provided, multiple submitters, no conflicts

Somatic classification of clinical impact:: None
Review status:: (0/4) 0 stars out of maximum of 4 stars
no assertion criteria provided

Somatic classification of oncogenicity:: None
Review status:: (0/4) 0 stars out of maximum of 4 stars
no assertion criteria provided

Record status:: current
Accession:: RCV000002581.15

Allele description [Variation Report for NM_207122.2(EXT2):c.744-2A>C]

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

Gene:

EXT2:exostosin glycosyltransferase 2 [Gene - OMIM - HGNC]

Variant type:

single nucleotide variant

Cytogenetic location:

11p11.2

Genomic location:

Preferred name:

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

HGVS:

NC_000011.10:g.44124787A>C
NG_007560.1:g.34239A>C
NM_000401.3:c.843-2A>C
NM_001178083.3:c.744-2A>C
NM_001389628.1:c.744-2A>C
NM_001389630.1:c.744-2A>C
NM_207122.2:c.744-2A>CMANE SELECT
LRG_494t1:c.843-2A>C
LRG_494t2:c.744-2A>C
LRG_494:g.34239A>C
NC_000011.9:g.44146337A>C
NM_207122.1:c.744-2A>C

Nucleotide change:

IVS4AS, A-C, -2

Links:

OMIM: 608210.0007; dbSNP: rs864309638

NCBI 1000 Genomes Browser:

rs864309638

Molecular consequence:

NM_000401.3:c.843-2A>C - splice acceptor variant - [Sequence Ontology: SO:0001574]
NM_001178083.3:c.744-2A>C - splice acceptor variant - [Sequence Ontology: SO:0001574]
NM_001389628.1:c.744-2A>C - splice acceptor variant - [Sequence Ontology: SO:0001574]
NM_001389630.1:c.744-2A>C - splice acceptor variant - [Sequence Ontology: SO:0001574]
NM_207122.2:c.744-2A>C - splice acceptor variant - [Sequence Ontology: SO:0001574]

Functional consequence:

exon loss [PubMedVariation Ontology: 0381]

Observations:

Condition(s)

Name:: Exostoses, multiple, type 2 (EXT2)
Synonyms:: EXOSTOSES, MULTIPLE, TYPE II
Identifiers:: MONDO: MONDO:0007586; MedGen: C1851413; Orphanet: 321; OMIM: 133701

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV000022739	OMIM	no assertion criteria provided	Pathogenic (May 1, 2009)	germline	literature only	PubMed (1) [See all records that cite this PMID]
SCV000957980	Labcorp Genetics (formerly Invitae), Labcorp	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Pathogenic (Apr 24, 2023)	germline	clinical testing	PubMed (5) [See all records that cite these PMIDs] 19344451, 16199547, 10679937, 19810120, 28492532
SCV001547507	Breda Genetics srl	criteria provided, single submitter (ACMG Guidelines, 2015)	Pathogenic (Mar 1, 2019)	germline	clinical testing	PubMed (1) [See all records that cite this PMID]

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV000022739

OMIM

no assertion criteria provided

Pathogenic
(May 1, 2009)

germline

literature only

PubMed (1)
[See all records that cite this PMID]

SCV000957980

Labcorp Genetics (formerly Invitae), Labcorp

criteria provided, single submitter

(Invitae Variant Classification Sherloc (09022015))

Pathogenic
(Apr 24, 2023)

germline

clinical testing

PubMed (5)
[See all records that cite these PMIDs]

SCV001547507

Breda Genetics srl

criteria provided, single submitter

(ACMG Guidelines, 2015)

Pathogenic
(Mar 1, 2019)

germline

clinical testing

PubMed (1)
[See all records that cite this PMID]

Help

Summary from all submissions

Ethnicity	Origin	Affected	Individuals	Families	Chromosomes tested	Number Tested	Family history	Method
not provided	germline	not provided	not provided	not provided	not provided	not provided	not provided	literature only
not provided	germline	yes	1	not provided	not provided	not provided	not provided	clinical testing
not provided	germline	unknown	not provided	not provided	not provided	not provided	not provided	clinical testing

Citations

PubMed

Nothing to display

See all PubMed Citations (6)

Details of each submission

From OMIM, SCV000022739.5

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	literature only	PubMed (1)

Description

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.

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	not provided	not provided	not provided	not provided		not provided	not provided	not provided	not provided

From Labcorp Genetics (formerly Invitae), Labcorp, SCV000957980.6

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (5)

Description

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).

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	unknown	not provided	not provided	not provided		not provided	not provided	not provided	not provided

From Breda Genetics srl, SCV001547507.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1		1	not provided	not provided	clinical testing	PubMed (1)

Description

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.

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	yes	not provided	not provided	not provided		1	not provided	not provided	not provided

Last Updated: Sep 29, 2024

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