Submissions for variant NM_207122.2(EXT2):c.627-2A>G

dbSNP: rs1064793854

Total submissions: 2

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000484382	SCV000567186	pathogenic	not provided	2015-07-23	criteria provided, single submitter	clinical testing	The c.627-2 A>G splice site variant in the EXT2 gene has been previously reported in association withherediatry multiple extoses (Gigante et al., 2001). This variant destroys the canonical splice acceptor site in intron 3, and is expected to cause abnormal gene splicing. It 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. Therefore, we consider this variant to be pathogenic.
Invitae	RCV001204484	SCV001375691	pathogenic	Exostoses, multiple, type 2	2023-09-05	criteria provided, single submitter	clinical testing	This sequence change affects an acceptor 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 hereditary multiple osteochondromatosis (PMID: 11668521). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 419409). 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.