NM_207122.2(EXT2):c.383G>A (p.Arg128Gln) AND Exostoses, multiple, type 2

Germline classification:: Conflicting interpretations of pathogenicity (3 submissions)
Last evaluated:: Apr 4, 2024
Review status:: criteria provided, conflicting classifications

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:: RCV001107844.15

Allele description [Variation Report for NM_207122.2(EXT2):c.383G>A (p.Arg128Gln)]

NM_207122.2(EXT2):c.383G>A (p.Arg128Gln)

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.383G>A (p.Arg128Gln)

HGVS:

NC_000011.10:g.44108095G>A
NG_007560.1:g.17547G>A
NM_000401.3:c.482G>A
NM_001178083.3:c.383G>A
NM_001389628.1:c.383G>A
NM_001389630.1:c.383G>A
NM_207122.2:c.383G>AMANE SELECT
NP_000392.3:p.Arg161Gln
NP_001171554.1:p.Arg128Gln
NP_001376557.1:p.Arg128Gln
NP_001376559.1:p.Arg128Gln
NP_997005.1:p.Arg128Gln
LRG_494t1:c.482G>A
LRG_494t2:c.383G>A
LRG_494:g.17547G>A
LRG_494p1:p.Arg161Gln
NC_000011.9:g.44129645G>A
NM_207122.1:c.383G>A

Protein change:

R128Q

Links:

dbSNP: rs771039412

NCBI 1000 Genomes Browser:

rs771039412

Molecular consequence:

NM_000401.3:c.482G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001178083.3:c.383G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001389628.1:c.383G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001389630.1:c.383G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_207122.2:c.383G>A - 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
SCV001265029	Illumina Laboratory Services, Illumina	criteria provided, single submitter (ICSL Variant Classification Criteria 13 December 2019)	Likely benign (Jan 13, 2018)	germline	clinical testing	Citation Link,
SCV001557938	Labcorp Genetics (formerly Invitae), Labcorp	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Uncertain significance (Sep 11, 2023)	germline	clinical testing	PubMed (1) [See all records that cite this PMID]
SCV004809972	Center for Genomic Medicine, King Faisal Specialist Hospital and Research Center	criteria provided, single submitter (ACMG Guidelines, 2015)	Likely benign (Apr 4, 2024)	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

SCV001265029

Illumina Laboratory Services, Illumina

criteria provided, single submitter

(ICSL Variant Classification Criteria 13 December 2019)

Likely benign
(Jan 13, 2018)

germline

clinical testing

Citation Link,

SCV001557938

Labcorp Genetics (formerly Invitae), Labcorp

criteria provided, single submitter

(Invitae Variant Classification Sherloc (09022015))

Uncertain significance
(Sep 11, 2023)

germline

clinical testing

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

SCV004809972

Center for Genomic Medicine, King Faisal Specialist Hospital and Research Center

criteria provided, single submitter

(ACMG Guidelines, 2015)

Likely benign
(Apr 4, 2024)

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

Citations

PubMed

Sherloc: a comprehensive refinement of the ACMG-AMP variant classification criteria.

Nykamp K, Anderson M, Powers M, Garcia J, Herrera B, Ho YY, Kobayashi Y, Patil N, Thusberg J, Westbrook M; Invitae Clinical Genomics Group., Topper S.

Genet Med. 2017 Oct;19(10):1105-1117. doi: 10.1038/gim.2017.37. Epub 2017 May 11. Erratum in: Genet Med. 2020 Jan;22(1):240. doi: 10.1038/s41436-019-0624-9.

PubMed [citation]

PMID:: 28492532
PMCID:: PMC5632818

Standards and guidelines for the interpretation of sequence variants: a joint consensus recommendation of the American College of Medical Genetics and Genomics and the Association for Molecular Pathology.

Richards S, Aziz N, Bale S, Bick D, Das S, Gastier-Foster J, Grody WW, Hegde M, Lyon E, Spector E, Voelkerding K, Rehm HL; ACMG Laboratory Quality Assurance Committee..

Genet Med. 2015 May;17(5):405-24. doi: 10.1038/gim.2015.30. Epub 2015 Mar 5.

PubMed [citation]

PMID:: 25741868
PMCID:: PMC4544753

Details of each submission

From Illumina Laboratory Services, Illumina, SCV001265029.1

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

Description

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as likely benign is not then subjected to further curation. The score for this variant resulted in a classification of likely benign for this disease.

#	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 Labcorp Genetics (formerly Invitae), Labcorp, SCV001557938.4

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

Description

This sequence change replaces arginine, which is basic and polar, with glutamine, which is neutral and polar, at codon 128 of the EXT2 protein (p.Arg128Gln). This variant is present in population databases (rs771039412, gnomAD 0.005%). 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: 879929). 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 not expected to disrupt EXT2 protein function. 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 Center for Genomic Medicine, King Faisal Specialist Hospital and Research Center, SCV004809972.1

#	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	germline	unknown	not provided	not provided	not provided		not provided	not provided	not provided	not provided

Last Updated: Sep 29, 2024

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