ClinVar Miner

Submissions for variant NM_207122.2(EXT2):c.744-2A>C

dbSNP: rs864309638
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Total submissions: 4
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Invitae RCV000002581 SCV000957980 pathogenic Exostoses, multiple, type 2 2023-04-24 criteria provided, single submitter clinical testing For these reasons, this variant has been classified as Pathogenic. Studies have shown that disruption of this splice site is associated with altered splicing resulting in multiple RNA products (PMID: 19344451). ClinVar contains an entry for this variant (Variation ID: 2477). Disruption of this splice site has been observed in individual(s) with hereditary multiple osteochondromatosis (PMID: 19344451; Invitae). This variant is not present in population databases (gnomAD no frequency). This sequence change affects an acceptor splice site in intron 4 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).
Breda Genetics srl RCV000002581 SCV001547507 pathogenic Exostoses, multiple, type 2 2019-03-01 criteria provided, single submitter clinical testing The variant c.843-2A>C in the EXT2 gene is reported as pathogenic for multiple exostoses type 2 in ClinVar (Variation ID: 2477). This variant has been originally identified by Heinritz et al. (2009) in a male patient who was reported to have also an affected son. This nucleotide substitution results in two different skipping events: either only exon 5 or exons 5 and 6. Loss of exon 5 results in a frameshift with premature termination 18 amino acids downstream (p.Pro249Argfs*18), while loss of exons 5 and 6 leads to the in-frame deletion p.Pro249_Arg360del (PMID: 19344451). This variant has not been reported in gnomAD, 1000 Genomes, NHLI Exome Sequencing Project (ESP), or LOVD database v.3.0.
PreventionGenetics, part of Exact Sciences RCV003398422 SCV004104843 pathogenic EXT2-related disorder 2023-08-04 criteria provided, single submitter clinical testing The EXT2 c.744-2A>C variant is predicted to disrupt the AG splice acceptor site and interfere with normal splicing. This variant has been reported in an individual with multiple osteochondromas (Heinritz et al. 2009. PubMed ID: 19344451). This variant has not been reported in a large population database (http://gnomad.broadinstitute.org), indicating this variant is rare. Variants that disrupt the consensus splice acceptor site in EXT2 are expected to be pathogenic. This variant is interpreted as pathogenic.
OMIM RCV000002581 SCV000022739 pathogenic Exostoses, multiple, type 2 2009-05-01 no assertion criteria provided literature only

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