NM_000401.3(EXT2):c.1121C>T (p.Pro374Leu) AND Multiple exostoses type 2

Clinical significance:Conflicting interpretations of pathogenicity, Likely benign(1);Uncertain significance(1) (Last evaluated: Oct 14, 2020)

Review status:1 star out of maximum of 4 stars

criteria provided, conflicting interpretations

Based on:
3 submissions [Details]
Record status:
current
Accession:
RCV000795903.5

Allele description [Variation Report for NM_000401.3(EXT2):c.1121C>T (p.Pro374Leu)]

NM_000401.3(EXT2):c.1121C>T (p.Pro374Leu)

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.1121C>T (p.Pro374Leu)
HGVS:
  • NC_000011.10:g.44126898C>T
  • NG_007560.1:g.36350C>T
  • NM_000401.3:c.1121C>T
  • NM_001178083.2:c.1022C>T
  • NM_207122.1:c.1022C>T
  • NP_000392.3:p.Pro374Leu
  • NP_001171554.1:p.Pro341Leu
  • NP_997005.1:p.Pro341Leu
  • LRG_494t1:c.1121C>T
  • LRG_494t2:c.1022C>T
  • LRG_494:g.36350C>T
  • LRG_494p1:p.Pro374Leu
  • LRG_494p2:p.Pro341Leu
  • NC_000011.9:g.44148448C>T
Protein change:
P341L
Links:
dbSNP: rs141035971
NCBI 1000 Genomes Browser:
rs141035971
Molecular consequence:
  • NM_000401.3:c.1121C>T - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001178083.2:c.1022C>T - missense variant - [Sequence Ontology: SO:0001583]
  • NM_207122.1:c.1022C>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
SCV000371844Illumina Clinical Services Laboratory,Illuminacriteria provided, single submitter
Likely benign
(Jan 12, 2018)
germlineclinical testing

Citation Link,

SCV000935384Invitaecriteria provided, single submitter
Uncertain significance
(Oct 14, 2020)
germlineclinical testing

PubMed (2)
[See all records that cite these PMIDs]

SCV001423440GenomeConnect, ClinGenno assertion providednot providedunknownphenotyping only

Summary from all submissions

EthnicityOriginAffectedIndividualsFamiliesChromosomes testedNumber TestedFamily historyMethod
not providedgermlineunknownnot providednot providednot providednot providednot providedclinical testing
not providedunknownunknownnot providednot providednot providednot providednot providedphenotyping only

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, SCV000371844.3

#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

From Invitae, SCV000935384.3

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

Description

This sequence change replaces proline with leucine at codon 341 of the EXT2 protein (p.Pro341Leu). The proline residue is highly conserved and there is a moderate physicochemical difference between proline and leucine. This variant is present in population databases (rs141035971, ExAC 0.06%), 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 disease. ClinVar contains an entry for this variant (Variation ID: 134215). 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: Probably Damaging; 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

From GenomeConnect, ClinGen, SCV001423440.1

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1not providednot providednot providednot providedphenotyping onlynot provided

Description

Variant interpretted as Uncertain significance and reported on 04-29-2017 by Lab or GTR ID 26957. GenomeConnect assertions are reported exactly as they appear on the patient-provided report from the testing laboratory. GenomeConnect staff make no attempt to reinterpret the clinical significance of the variant.

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

Last Updated: Mar 7, 2021

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