Submissions for variant NM_000127.3(EXT1):c.1021A>T (p.Arg341Trp)

dbSNP: rs1554580149

Total submissions: 2

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000520066	SCV000620510	likely pathogenic	not provided	2017-09-27	criteria provided, single submitter	clinical testing	The R341W variant in the EXT1 gene has not been published as a pathogenic variant, nor has it been reported as a benign variant to our knowledge. The variant has been observed to occur apparently de novo in an individual at GeneDx. The variant is not observed in large population cohorts (Lek et al., 2016; 1000 Genomes Consortium et al., 2015; Exome Variant Server). R341W 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, and in silico analysis predicts this variant is probably damaging to the protein structure/function. In summary, we consider this variant to be likely pathogenic.
Invitae	RCV001206165	SCV001377461	likely pathogenic	Multiple congenital exostosis	2022-11-29	criteria provided, single submitter	clinical testing	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. This variant disrupts the p.Arg341 amino acid residue in EXT1. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 19810120, 23439489). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. 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. ClinVar contains an entry for this variant (Variation ID: 451765). This missense change has been observed in individual(s) with clinical features of hereditary multiple osteochondromas (Invitae). This variant is not present in population databases (gnomAD no frequency). This sequence change replaces arginine, which is basic and polar, with tryptophan, which is neutral and slightly polar, at codon 341 of the EXT1 protein (p.Arg341Trp).