NM_000401.3(EXT2):c.344A>C (p.Asp115Ala) AND Multiple exostoses type 2

Clinical significance:Conflicting interpretations of pathogenicity, Likely benign(1);Uncertain significance(1) (Last evaluated: Sep 18, 2019)

Review status:1 star out of maximum of 4 stars

criteria provided, conflicting interpretations

Based on:
2 submissions [Details]
Record status:
current
Accession:
RCV000328182.4

Allele description [Variation Report for NM_000401.3(EXT2):c.344A>C (p.Asp115Ala)]

NM_000401.3(EXT2):c.344A>C (p.Asp115Ala)

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.344A>C (p.Asp115Ala)
HGVS:
  • NC_000011.10:g.44107957A>C
  • NG_007560.1:g.17409A>C
  • NM_000401.3:c.344A>C
  • NM_001178083.2:c.245A>C
  • NM_207122.1:c.245A>C
  • NP_000392.3:p.Asp115Ala
  • NP_001171554.1:p.Asp82Ala
  • NP_997005.1:p.Asp82Ala
  • LRG_494t1:c.344A>C
  • LRG_494t2:c.245A>C
  • LRG_494:g.17409A>C
  • LRG_494p1:p.Asp115Ala
  • LRG_494p2:p.Asp82Ala
  • NC_000011.9:g.44129507A>C
Protein change:
D115A
Links:
dbSNP: rs534539796
NCBI 1000 Genomes Browser:
rs534539796
Molecular consequence:
  • NM_000401.3:c.344A>C - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001178083.2:c.245A>C - missense variant - [Sequence Ontology: SO:0001583]
  • NM_207122.1:c.245A>C - 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
SCV000371828Illumina Clinical Services Laboratory,Illuminacriteria provided, single submitter
Likely benign
(Apr 27, 2017)
germlineclinical testing

Citation Link,

SCV001380961Invitaecriteria provided, single submitter
Uncertain significance
(Sep 18, 2019)
germlineclinical testing

PubMed (2)
[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

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 Illumina Clinical Services Laboratory,Illumina, SCV000371828.3

#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 allowed determination this variant is unlikely to cause disease. Therefore, this variant is classified as likely benign.

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

From Invitae, SCV001380961.2

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1not providednot providednot providednot providedclinical testing PubMed (2)

Description

This sequence change replaces aspartic acid with alanine at codon 82 of the EXT2 protein (p.Asp82Ala). The aspartic acid residue is moderately conserved and there is a moderate physicochemical difference between aspartic acid and alanine. This variant is present in population databases (rs534539796, ExAC 0.05%), and has an allele count higher than expected for a pathogenic variant (PMID: 28166811). This variant has not been reported in the literature in individuals with EXT2-related conditions. ClinVar contains an entry for this variant (Variation ID: 304575). Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: Deleterious; PolyPhen-2: Benign; Align-GVGD: Class C0). 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: Apr 12, 2021

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