NM_207122.2(EXT2):c.667C>T (p.Arg223Trp) AND Exostoses, multiple, type 2

Germline classification:: Uncertain significance (2 submissions)
Last evaluated:: Mar 3, 2024
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:: RCV001941353.6

Allele description [Variation Report for NM_207122.2(EXT2):c.667C>T (p.Arg223Trp)]

NM_207122.2(EXT2):c.667C>T (p.Arg223Trp)

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.667C>T (p.Arg223Trp)

HGVS:

NC_000011.10:g.44114225C>T
NG_007560.1:g.23677C>T
NM_000401.3:c.766C>T
NM_001178083.3:c.667C>T
NM_001389628.1:c.667C>T
NM_001389630.1:c.667C>T
NM_207122.2:c.667C>TMANE SELECT
NP_000392.3:p.Arg256Trp
NP_001171554.1:p.Arg223Trp
NP_001376557.1:p.Arg223Trp
NP_001376559.1:p.Arg223Trp
NP_997005.1:p.Arg223Trp
LRG_494t1:c.766C>T
LRG_494:g.23677C>T
LRG_494p1:p.Arg256Trp
NC_000011.9:g.44135775C>T
NM_207122.1:c.667C>T

Protein change:

R223W

Links:

dbSNP: rs201062014

NCBI 1000 Genomes Browser:

rs201062014

Molecular consequence:

NM_000401.3:c.766C>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001178083.3:c.667C>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001389628.1:c.667C>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001389630.1:c.667C>T - missense variant - [Sequence Ontology: SO:0001583]
NM_207122.2:c.667C>T - missense variant - [Sequence Ontology: SO:0001583]

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
SCV002223603	Labcorp Genetics (formerly Invitae), Labcorp	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Uncertain significance (Nov 27, 2023)	germline	clinical testing	PubMed (5) [See all records that cite these PMIDs] 12490068, 17589361, 18165274, 23262345, 28492532
SCV004192807	Baylor Genetics	criteria provided, single submitter (ACMG Guidelines, 2015)	Uncertain significance (Mar 3, 2024)	unknown	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

SCV002223603

Labcorp Genetics (formerly Invitae), Labcorp

criteria provided, single submitter

(Invitae Variant Classification Sherloc (09022015))

Uncertain significance
(Nov 27, 2023)

germline

clinical testing

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

SCV004192807

Baylor Genetics

criteria provided, single submitter

(ACMG Guidelines, 2015)

Uncertain significance
(Mar 3, 2024)

unknown

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	unknown	not provided	not provided	not provided	not provided	not provided	clinical testing
not provided	unknown	unknown	not provided	not provided	not provided	not provided	not provided	clinical testing

Citations

PubMed

Mutation screening of the EXT genes in patients with hereditary multiple exostoses in Taiwan.

Shi YR, Wu JY, Hsu YA, Lee CC, Tsai CH, Tsai FJ.

Genet Test. 2002 Fall;6(3):237-43.

PubMed [citation]

PMID:: 12490068

Evaluation of the anatomic burden of patients with hereditary multiple exostoses.

Alvarez CM, De Vera MA, Heslip TR, Casey B.

Clin Orthop Relat Res. 2007 Sep;462:73-9.

PubMed [citation]

PMID:: 17589361

See all PubMed Citations (6)

Details of each submission

From Labcorp Genetics (formerly Invitae), Labcorp, SCV002223603.3

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

Description

This sequence change replaces arginine, which is basic and polar, with tryptophan, which is neutral and slightly polar, at codon 223 of the EXT2 protein (p.Arg223Trp). This variant is present in population databases (rs201062014, gnomAD 0.006%). This variant has not been reported in the literature in individuals affected with EXT2-related conditions. ClinVar contains an entry for this variant (Variation ID: 1441831). 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) performed at Invitae indicates that this missense variant is expected to disrupt EXT2 protein function with a positive predictive value of 80%. This variant disrupts the p.Arg223 amino acid residue in EXT2. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 12490068, 17589361, 18165274, 23262345). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance.

#	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 Baylor Genetics, SCV004192807.2

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

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

Last Updated: Oct 20, 2024

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