NM_000401.3(EXT2):c.619A>C (p.Met207Leu) AND Multiple exostoses type 2

Clinical significance:Conflicting interpretations of pathogenicity, Benign(1);Uncertain significance(1) (Last evaluated: Aug 10, 2020)

Review status:1 star out of maximum of 4 stars

criteria provided, conflicting interpretations

Based on:
2 submissions [Details]
Record status:

Allele description [Variation Report for NM_000401.3(EXT2):c.619A>C (p.Met207Leu)]

NM_000401.3(EXT2):c.619A>C (p.Met207Leu)

EXT2:exostosin glycosyltransferase 2 [Gene - OMIM - HGNC]
Variant type:
single nucleotide variant
Cytogenetic location:
Genomic location:
Preferred name:
NM_000401.3(EXT2):c.619A>C (p.Met207Leu)
  • NC_000011.10:g.44108232A>C
  • NG_007560.1:g.17684A>C
  • NM_000401.3:c.619A>C
  • NM_001178083.2:c.520A>C
  • NM_207122.1:c.520A>C
  • NP_000392.3:p.Met207Leu
  • NP_001171554.1:p.Met174Leu
  • NP_997005.1:p.Met174Leu
  • LRG_494t1:c.619A>C
  • LRG_494t2:c.520A>C
  • LRG_494:g.17684A>C
  • LRG_494p1:p.Met207Leu
  • LRG_494p2:p.Met174Leu
  • NC_000011.9:g.44129782A>C
Protein change:
dbSNP: rs111589746
NCBI 1000 Genomes Browser:
Molecular consequence:
  • NM_000401.3:c.619A>C - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001178083.2:c.520A>C - missense variant - [Sequence Ontology: SO:0001583]
  • NM_207122.1:c.520A>C - missense variant - [Sequence Ontology: SO:0001583]


Multiple exostoses type 2 (EXT2)
MONDO: MONDO:0007586; MedGen: C1851413; Orphanet: 321; OMIM: 133701

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Assertion and evidence details

Submission AccessionSubmitterReview Status
(Assertion method)
Clinical Significance
(Last evaluated)
SCV000371833Illumina Clinical Services Laboratory,Illuminacriteria provided, single submitter
(Jan 12, 2018)
germlineclinical testing

Citation Link,

SCV001233882Invitaecriteria provided, single submitter
Uncertain significance
(Aug 10, 2020)
germlineclinical testing

PubMed (3)
[See all records that cite these PMIDs]

Summary from all submissions

EthnicityOriginAffectedIndividualsFamiliesChromosomes testedNumber TestedFamily historyMethod
not providedgermlineunknownnot providednot providednot providednot providednot providedclinical testing



Pathogenic variant burden in the ExAC database: an empirical approach to evaluating population data for clinical variant interpretation.

Kobayashi Y, Yang S, Nykamp K, Garcia J, Lincoln SE, Topper SE.

Genome Med. 2017 Feb 6;9(1):13. doi: 10.1186/s13073-017-0403-7.

PubMed [citation]

Comparison of fluorescent single-strand conformation polymorphism analysis and denaturing high-performance liquid chromatography for detection of EXT1 and EXT2 mutations in hereditary multiple exostoses.

Dobson-Stone C, Cox RD, Lonie L, Southam L, Fraser M, Wise C, Bernier F, Hodgson S, Porter DE, Simpson AH, Monaco AP.

Eur J Hum Genet. 2000 Jan;8(1):24-32.

PubMed [citation]
See all PubMed Citations (3)

Details of each submission

From Illumina Clinical Services Laboratory,Illumina, SCV000371833.3

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1not providednot providednot providednot providedclinical testingnot provided


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 benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease.

OriginAffectedNumber testedTissuePurposeMethodIndividualsAllele frequencyFamiliesCo-occurrences
1germlineunknownnot providednot providednot providednot providednot providednot providednot provided

From Invitae, SCV001233882.2

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1not providednot providednot providednot providedclinical testing PubMed (3)


This sequence change replaces methionine with leucine at codon 174 of the EXT2 protein (p.Met174Leu). The methionine residue is weakly conserved and there is a small physicochemical difference between methionine and leucine. This variant is present in population databases (rs111589746, ExAC 0.05%), and has an allele count higher than expected for a pathogenic variant (PMID: 28166811). This variant has been observed in an individual affected with clinical features of hereditary multiple exostoses (PMID: 10713884). ClinVar contains an entry for this variant (Variation ID: 134208). Algorithms developed to predict the effect of missense changes on protein structure and function output the following: SIFT: Tolerated; PolyPhen-2: Benign; Align-GVGD: Class C0. The leucine amino acid residue is found in multiple mammalian species, suggesting that this missense change does not adversely affect protein function. These predictions have not been confirmed by published functional studies and their clinical significance is uncertain. 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.

OriginAffectedNumber testedTissuePurposeMethodIndividualsAllele frequencyFamiliesCo-occurrences
1germlineunknownnot providednot providednot providednot providednot providednot providednot provided

Last Updated: Mar 14, 2021

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