NM_000401.3(EXT2):c.2015C>T (p.Thr672Met) AND Multiple exostoses type 2

Clinical significance:Conflicting interpretations of pathogenicity, Likely benign(1);Uncertain significance(1) (Last evaluated: Nov 16, 2018)

Review status:1 star out of maximum of 4 stars

criteria provided, conflicting interpretations

Based on:
2 submissions [Details]
Record status:
current
Accession:
RCV000806392.2

Allele description [Variation Report for NM_000401.3(EXT2):c.2015C>T (p.Thr672Met)]

NM_000401.3(EXT2):c.2015C>T (p.Thr672Met)

Gene:
EXT2:exostosin glycosyltransferase 2 [Gene - OMIM - HGNC]
Variant type:
single nucleotide variant
Cytogenetic location:
11p11.2
Genomic location:
Preferred name:
NM_000401.3(EXT2):c.2015C>T (p.Thr672Met)
Other names:
EXT2, THR672MET (rs138722406)
HGVS:
  • NC_000011.10:g.44234224C>T
  • NG_007560.1:g.143676C>T
  • NM_000401.3:c.2015C>T
  • NM_001178083.2:c.1946C>T
  • NM_207122.1:c.1916C>T
  • NP_000392.3:p.Thr672Met
  • NP_001171554.1:p.Thr649Met
  • NP_997005.1:p.Thr639Met
  • LRG_494t1:c.2015C>T
  • LRG_494t2:c.1916C>T
  • LRG_494:g.143676C>T
  • LRG_494p1:p.Thr672Met
  • LRG_494p2:p.Thr639Met
  • NC_000011.9:g.44255774C>T
Protein change:
T639M; THR672MET
Links:
OMIM: 608210.0011; dbSNP: rs138722406
NCBI 1000 Genomes Browser:
rs138722406
Molecular consequence:
  • NM_000401.3:c.2015C>T - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001178083.2:c.1946C>T - missense variant - [Sequence Ontology: SO:0001583]
  • NM_207122.1:c.1916C>T - missense variant - [Sequence Ontology: SO:0001583]

Condition(s)

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

Recent activity

Your browsing activity is empty.

Activity recording is turned off.

Turn recording back on

See more...

Assertion and evidence details

Submission AccessionSubmitterReview Status
(Assertion method)
Clinical Significance
(Last evaluated)
OriginMethodCitations
SCV000946387Invitaecriteria provided, single submitter
Uncertain significance
(Nov 16, 2018)
germlineclinical testing

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

SCV001259400Illumina Clinical Services Laboratory,Illuminacriteria provided, single submitter
Likely benign
(Jan 13, 2018)
germlineclinical testing

Citation Link

Summary from all submissions

EthnicityOriginAffectedIndividualsFamiliesChromosomes testedNumber TestedFamily historyMethod
not providedgermlineunknownnot providednot providednot providednot providednot providedclinical 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):240-242.

PubMed [citation]
PMID:
28492532
PMCID:
PMC5632818

Details of each submission

From Invitae, SCV000946387.1

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

Description

This sequence change replaces threonine with methionine at codon 639 of the EXT2 protein (p.Thr639Met). The threonine residue is highly conserved and there is a moderate physicochemical difference between threonine and methionine. This variant is present in population databases (rs138722406, ExAC 0.01%). This variant has not been reported in the literature in individuals with EXT2-related disease. ClinVar contains an entry for this variant (Variation ID: 134205). Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be disruptive, but 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.

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

From Illumina Clinical Services Laboratory,Illumina, SCV001259400.1

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

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

Last Updated: Aug 27, 2021

Support Center