Submissions for variant NM_000127.3(EXT1):c.1746G>A (p.Trp582Ter)

dbSNP: rs1586990398

Total submissions: 2

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV001008654	SCV001168432	pathogenic	not provided	2019-02-25	criteria provided, single submitter	clinical testing	The W582X nonsense variant in the EXT1 gene has been reported previously in association with hereditary multiple exostoses (Francannet et al., 2001), and its presence is consistent with the diagnosis in this patient. This pathogenic variant is predicted to cause loss of normal protein function either through protein truncation or nonsense-mediated mRNA decay. The W582X variant is not observed in large population cohorts (Lek et al., 2016). A different nucleotide change (c.1745 G>A) leading to the same nonsense variant has been reported as pathogenic in the published literature in association with hereditary multiple exostoses (Francannet et al., 2001). In summary, we consider this variant to be pathogenic.
Invitae	RCV001226441	SCV001398754	pathogenic	Multiple congenital exostosis	2022-03-20	criteria provided, single submitter	clinical testing	For these reasons, this variant has been classified as Pathogenic. ClinVar contains an entry for this variant (Variation ID: 817515). This premature translational stop signal has been observed in individual(s) with hereditary multiple osteochondromatosis (PMID: 11432960, 19810120). This variant is not present in population databases (gnomAD no frequency). This sequence change creates a premature translational stop signal (p.Trp582*) in the EXT1 gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in EXT1 are known to be pathogenic (PMID: 10679937, 11391482, 19810120).