NM_207122.2(EXT2):c.605C>T (p.Ala202Val) AND Multiple exostoses type 2

Clinical significance:Conflicting interpretations of pathogenicity, Benign(1);Uncertain significance(1) (Last evaluated: Mar 14, 2020)

Review status:1 star out of maximum of 4 stars

criteria provided, conflicting interpretations

Based on:
2 submissions [Details]
Record status:
current
Accession:
RCV001107846.2

Allele description [Variation Report for NM_207122.2(EXT2):c.605C>T (p.Ala202Val)]

NM_207122.2(EXT2):c.605C>T (p.Ala202Val)

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.605C>T (p.Ala202Val)
HGVS:
  • NC_000011.10:g.44109262C>T
  • NG_007560.1:g.18714C>T
  • NM_000401.3:c.704C>T
  • NM_001178083.2:c.605C>T
  • NM_207122.2:c.605C>TMANE SELECT
  • NP_000392.3:p.Ala235Val
  • NP_001171554.1:p.Ala202Val
  • NP_997005.1:p.Ala202Val
  • LRG_494t1:c.704C>T
  • LRG_494t2:c.605C>T
  • LRG_494:g.18714C>T
  • LRG_494p1:p.Ala235Val
  • NC_000011.9:g.44130812C>T
  • NM_207122.1:c.605C>T
Protein change:
A202V
Links:
Molecular consequence:
  • NM_000401.3:c.704C>T - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001178083.2:c.605C>T - missense variant - [Sequence Ontology: SO:0001583]
  • NM_207122.2:c.605C>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

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Assertion and evidence details

Submission AccessionSubmitterReview Status
(Assertion method)
Clinical Significance
(Last evaluated)
OriginMethodCitations
SCV001265031Illumina Clinical Services Laboratory,Illuminacriteria provided, single submitter
Benign
(Apr 28, 2017)
germlineclinical testing

Citation Link,

SCV001534145Invitaecriteria provided, single submitter
Uncertain significance
(Mar 14, 2020)
germlineclinical testing

PubMed (4)
[See all records that cite these PMIDs]

Summary from all submissions

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

Citations

PubMed

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]
PMID:
28166811
PMCID:
PMC5295186

Mutation frequencies of EXT1 and EXT2 in 43 Japanese families with hereditary multiple exostoses.

Seki H, Kubota T, Ikegawa S, Haga N, Fujioka F, Ohzeki S, Wakui K, Yoshikawa H, Takaoka K, Fukushima Y.

Am J Med Genet. 2001 Feb 15;99(1):59-62.

PubMed [citation]
PMID:
11170095
See all PubMed Citations (4)

Details of each submission

From Illumina Clinical Services Laboratory,Illumina, SCV001265031.1

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

Description

This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). No publications were found based on this search. Allele frequency data from public databases was too high to be consistent with this variant causing disease. Therefore, this variant is classified as benign.

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

From Invitae, SCV001534145.1

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1not providednot providednot providednot providedclinical testing PubMed (4)

Description

This sequence change replaces alanine with valine at codon 202 of the EXT2 protein (p.Ala202Val). The alanine residue is highly conserved and there is a small physicochemical difference between alanine and valine. This variant is present in population databases (rs771803942, ExAC 0.1%), and has an allele count higher than expected for a pathogenic variant (PMID: 28166811). This variant has been observed in individuals affected with multiple osteochondromatosis (PMID: 11170095, 26961984). 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 tolerated, 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

Last Updated: Mar 28, 2021

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