Submissions for variant NM_207122.2(EXT2):c.743+1G>A

dbSNP: rs886039567

Total submissions: 2

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000254884	SCV000322415	pathogenic	not provided	2016-03-09	criteria provided, single submitter	clinical testing	The c.743+1 G>A splice site variant in the EXT2 gene has been previously reported in association with hereditary multiple exostoses (Vink et al., 2005; Tian et al., 2014), and is consistent with the diagnosis in this patient. The 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. Functional studies by Tian C. et al. have shown that c.743+1 G>A destroys the canonical splice donor site in intron 4 and causes abnormal gene splicing. Patients in this study also displayed significantly lowered EXT2 mRNA and protein levels compared to controls (Tian et al., 2014).
Invitae	RCV001211363	SCV001382900	pathogenic	Exostoses, multiple, type 2	2019-08-30	criteria provided, single submitter	clinical testing	For these reasons, this variant has been classified as Pathogenic. Donor and acceptor splice site variants typically lead to a loss of protein function (PMID: 16199547), and loss-of-function variants in EXT2 are known to be pathogenic (PMID: 10679937, 19810120). Experimental studies have shown that this variant disrupts mRNA splicing (PMID:24728384). Disruption of this splice site has been observed in individuals and families affected with hereditary multiple exostoses (PMID:15586175, 24728384). ClinVar contains an entry for this variant (Variation ID: 265474). This variant is not present in population databases (ExAC no frequency). This sequence change affects a donor splice site in intron 4 of the EXT2 gene. It is expected to disrupt RNA splicing and likely results in an absent or disrupted protein product.