Submissions for variant NM_000127.3(EXT1):c.803G>A (p.Gly268Glu)

dbSNP: rs886039352

Total submissions: 3

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000255528	SCV000321609	likely pathogenic	not provided	2017-03-22	criteria provided, single submitter	clinical testing	The G268E variant has not been published as a pathogenic variant, nor has it been reported as a benign polymorphism to our knowledge. The G268E variant was not observed in approximately 6,500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, indicating it is not a common benign variant in these populations. The G268E variant has been observed apparently de novo and also segregated in affected family members at GeneDx. It 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 that is conserved across species. Another variant at this position, G268R, has been reported in the literature in association with multiple osteochondromas (Jennes et al., 2009). Missense variants in nearby residues (L264P, R270W, Y271N, Y271H, Y271C) have also been reported in the Human Gene Mutation Database in association with EXT1-related disorders (Stenson et al., 2014), supporting the functional importance of this region of the protein. Therefore, G268E is interpreted to be a likely pathogenic variant.
Labcorp Genetics (formerly Invitae), Labcorp	RCV001859476	SCV002236637	pathogenic	Multiple congenital exostosis	2021-05-29	criteria provided, single submitter	clinical testing	Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is expected to disrupt EXT1 protein function. This variant disrupts the p.p.Gly268 amino acid residue in EXT1. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 19810120, Invitae). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. For these reasons, this variant has been classified as Pathogenic. This variant has been observed in individual(s) with multiple osteochondromatosis (PMID: 29529714). ClinVar contains an entry for this variant (Variation ID: 265126). This sequence change replaces glycine with glutamic acid at codon 268 of the EXT1 protein (p.Gly268Glu). The glycine residue is highly conserved and there is a moderate physicochemical difference between glycine and glutamic acid. This variant is not present in population databases (ExAC no frequency).
Palindrome, Gene Kavoshgaran Aria	RCV004689697	SCV005186181	pathogenic	Exostoses, multiple, type 1	2024-07-10	criteria provided, single submitter	clinical testing