ClinVar Miner

Submissions for variant NM_000127.3(EXT1):c.1018C>T (rs119103290)

Minimum review status: Collection method:
Minimum conflict level:
ClinVar version:
Total submissions: 4
Download table as spreadsheet
Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000255752 SCV000321612 pathogenic not provided 2019-01-18 criteria provided, single submitter clinical testing The R340C variant has been published previously in association with hereditary multiple exostoses (HME) and observed apparently de novo (Philippe et al., 1997; Zuntini et al., 2010; Delgado et al., 2014). The variant is not observed in large population cohorts (Lek et al., 2016). R340C is a non-conservative amino acid substitution, which is likely to impact secondary protein structure as these residues differ in polarity, charge, size and/or other properties. This substitution occurs at a position within the lumen domain that is conserved across species, and in silico analysis predicts this variant is probably damaging to the protein structure/function. Additionally, functional studies have shown that R340C disrupts the activity of the EXT1/EXT2 protein complex (McCormick et al., 1998; McCormick et al., 2000). Missense variants in the same residue (R340S/H/P/L) and in nearby residues (L335R, P337R, G339D/V, R341G/S, G343R/W, S344F) have been reported in the Human Gene Mutation Database in association with HME (Stenson et al., 2014), supporting the functional importance of this region of the protein. In summary, we consider this to be a pathogenic variant.
Invitae RCV000002606 SCV000814569 pathogenic Multiple congenital exostosis 2020-10-01 criteria provided, single submitter clinical testing This sequence change replaces arginine with cysteine at codon 340 of the EXT1 protein (p.Arg340Cys). The arginine residue is highly conserved and there is a large physicochemical difference between arginine and cysteine. This variant is not present in population databases (ExAC no frequency). This variant has been reported in several individuals affected with multiple osteochondromas/exostoses (PMID: 11432960, 16283885, 25230886, 22258776, 20418910), including at least one individual in which this variant was reported to arise de novo (PMID: 9326317). ClinVar contains an entry for this variant (Variation ID: 2500). Experimental studies have shown that this missense change abrogates heparan sulfate biosynthesis and disrupts the activity of the EXT1/EXT2 protein complex (PMID: 10679296, 10639137, 9620772). Different missense substitutions at this codon (p.Arg340His and p.Arg340Leu) have been determined to be pathogenic (PMID: 9521425, 26961984, 26239617, 8981950, 18330718, 26961984, 18165274, 19810120, 11391482). This suggests that the arginine residue is critical for EXT1 protein function and that other missense substitutions at this position may also be pathogenic. For these reasons, this variant has been classified as Pathogenic.
Clinical Genetics Karolinska University Hospital,Karolinska University Hospital RCV000255752 SCV001450412 likely pathogenic not provided 2019-02-07 criteria provided, single submitter clinical testing
OMIM RCV001003500 SCV000022764 pathogenic Multiple exostoses type 1 1998-06-01 no assertion criteria provided literature only

The information on this website is not intended for direct diagnostic use or medical decision-making without review by a genetics professional. Individuals should not change their health behavior solely on the basis of information contained on this website. Neither the University of Utah nor the National Institutes of Health independently verfies the submitted information. If you have questions about the information contained on this website, please see a health care professional.