Submissions for variant NM_207122.2(EXT2):c.626+1G>A

dbSNP: rs1057521132

Total submissions: 2

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000599186	SCV000709805	pathogenic	not provided	2018-02-16	criteria provided, single submitter	clinical testing	The c.626+1 G>A splice site variant in the EXT2 gene has been previously reported in at least one individual with multiple exostoses (Vink et al., 2005; Wuyts et al., 2005). This variant destroys the canonical splice donor site in intron 3, and is expected to cause abnormal gene splicing. This variant is not observed in large population cohorts (Lek et al., 2016). Alternate nucleotide changes at the same position (c.626+1G>T, c.626+1G>C) have been reported in association with hereditary multiple exostoses (Lonie et al., 2006; Xu et al., 2017).
Invitae	RCV001062683	SCV001227498	pathogenic	Exostoses, multiple, type 2	2020-02-06	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). Disruption of this splice site has been observed in individuals affected with multiple osteochondromas (PMID: 15586175, 17041877, 29529714, 28849184). This splice site is also known as c.725+1G in the literature. ClinVar contains an entry for this variant (Variation ID: 503618). This variant is not present in population databases (ExAC no frequency). This sequence change affects a donor splice site in intron 3 of the EXT2 gene. It is expected to disrupt RNA splicing and likely results in an absent or disrupted protein product.