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

dbSNP: rs1057521132

Total submissions: 2

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000443576	SCV000521160	likely pathogenic	not provided	2016-06-21	criteria provided, single submitter	clinical testing	The c.626+1 G>T variant has been published previosuly in association with multiple osteochondromas (Lonie et al., 2006). 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. While several in-silico splice prediction models predict that c.626+1 G>T destroys the natural splice donor site in intron 3, the adjacent exon 3 remains in-frame. In the absence of RNA/functional studies, the actual effect of this sequence change is unknown. Therefore, this variant is likely pathogenic; however, the possibility that it is benign cannot be excluded.
Invitae	RCV003497846	SCV004294764	pathogenic	Exostoses, multiple, type 2	2023-10-06	criteria provided, single submitter	clinical testing	This sequence change affects a donor splice site in intron 3 of the EXT2 gene. It is expected to disrupt RNA splicing. Variants that disrupt the donor or acceptor splice site 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). This variant is not present in population databases (gnomAD no frequency). Disruption of this splice site has been observed in individual(s) with multiple osteochondromas (PMID: 17041877). ClinVar contains an entry for this variant (Variation ID: 381659). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. For these reasons, this variant has been classified as Pathogenic.