NM_000127.3(EXT1):c.1064_1065delinsAT (p.Cys355Tyr) AND Multiple congenital exostosis

Germline classification:: Likely pathogenic (1 submission)
Last evaluated:: Feb 27, 2023
Review status:: 1 star out of maximum of 4 stars
criteria provided, single submitter

Somatic classification of clinical impact:: None
Review status:: (0/4) 0 stars out of maximum of 4 stars
no assertion criteria provided

Somatic classification of oncogenicity:: None
Review status:: (0/4) 0 stars out of maximum of 4 stars
no assertion criteria provided

Record status:: current
Accession:: RCV003604723.2

Allele description [Variation Report for NM_000127.3(EXT1):c.1064_1065delinsAT (p.Cys355Tyr)]

NM_000127.3(EXT1):c.1064_1065delinsAT (p.Cys355Tyr)

Gene:

EXT1:exostosin glycosyltransferase 1 [Gene - OMIM - HGNC]

Variant type:

Indel

Cytogenetic location:

8q24.11

Genomic location:

Preferred name:

NM_000127.3(EXT1):c.1064_1065delinsAT (p.Cys355Tyr)

HGVS:

NC_000008.11:g.117835543_117835544delinsAT
NG_007455.2:g.281276_281277delinsAT
NM_000127.3:c.1064_1065delinsATMANE SELECT
NP_000118.2:p.Cys355Tyr
NP_000118.2:p.Cys355Tyr
LRG_493t1:c.1064_1065delGCinsAT
LRG_493:g.281276_281277delinsAT
LRG_493p1:p.Cys355Tyr
NC_000008.10:g.118847782_118847783delinsAT
NM_000127.2:c.1064_1065delGCinsAT

Protein change:

C355Y

Molecular consequence:

NM_000127.3:c.1064_1065delinsAT - missense variant - [Sequence Ontology: SO:0001583]

Condition(s)

Name:: Multiple congenital exostosis (EXT)
Synonyms:: MULTIPLE CARTILAGINOUS EXOSTOSES; Hereditary multiple osteochondromas; Multiple exostoses; See all synonyms [MedGen]
Identifiers:: MONDO: MONDO:0005508; MedGen: C0015306; Orphanet: 321; OMIM: PS133700; Human Phenotype Ontology: HP:0002762

Recent activity

Clear Turn Off Turn On

Your browsing activity is empty.

Activity recording is turned off.

Turn recording back on

Help

Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV004500002	Labcorp Genetics (formerly Invitae), Labcorp	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Likely pathogenic (Feb 27, 2023)	germline	clinical testing	PubMed (4) [See all records that cite these PMIDs] 17301954, 26961984, 33414810, 28492532

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV004500002

Labcorp Genetics (formerly Invitae), Labcorp

criteria provided, single submitter

(Invitae Variant Classification Sherloc (09022015))

Likely pathogenic
(Feb 27, 2023)

germline

clinical testing

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

Help

Summary from all submissions

Ethnicity	Origin	Affected	Individuals	Families	Chromosomes tested	Number Tested	Family history	Method
not provided	germline	unknown	not provided	not provided	not provided	not provided	not provided	clinical testing

Citations

PubMed

A combined analytical approach reveals novel EXT1/2 gene mutations in a large cohort of Italian multiple osteochondromas patients.

Signori E, Massi E, Matera MG, Poscente M, Gravina C, Falcone G, Rosa MA, Rinaldi M, Wuyts W, Seripa D, Dallapiccola B, Fazio VM.

Genes Chromosomes Cancer. 2007 May;46(5):470-7.

PubMed [citation]

PMID:: 17301954

Large-scale mutational analysis in the EXT1 and EXT2 genes for Japanese patients with multiple osteochondromas.

Ishimaru D, Gotoh M, Takayama S, Kosaki R, Matsumoto Y, Narimatsu H, Sato T, Kimata K, Akiyama H, Shimizu K, Matsumoto K.

BMC Genet. 2016 Mar 9;17:52. doi: 10.1186/s12863-016-0359-4.

PubMed [citation]

PMID:: 26961984
PMCID:: PMC4784393

See all PubMed Citations (4)

Details of each submission

From Labcorp Genetics (formerly Invitae), Labcorp, SCV004500002.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (4)

Description

This sequence change replaces cysteine, which is neutral and slightly polar, with tyrosine, which is neutral and polar, at codon 355 of the EXT1 protein (p.Cys355Tyr). Information on the frequency of this variant in the gnomAD database is not available, as this variant may be reported differently in the database. This missense change has been observed in individual(s) with EXT1-related conditions (PMID: 26961984; Invitae). An algorithm developed to predict the effect of missense changes on protein structure and function (PolyPhen-2) suggests that this variant is likely to be disruptive. This variant disrupts the p.Cys355 amino acid residue in EXT1. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 17301954, 26961984, 33414810). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic.

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	unknown	not provided	not provided	not provided		not provided	not provided	not provided	not provided

Last Updated: Sep 29, 2024

ClinVar

Relating variation to medicine