ClinVar Miner

Submissions for variant NM_001114753.3(ENG):c.992-2A>G

dbSNP: rs1588580932
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Total submissions: 4
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Invitae RCV000821165 SCV000961912 pathogenic Hereditary hemorrhagic telangiectasia 2018-08-25 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 ENG are known to be pathogenic (PMID: 15879500, 20656886, 22385575). Different variants affecting this acceptor dinucleotide (c.992-1G>C and c.992-1G>A) have been observed in affected individuals (PMID: 19270816, 16705692). This suggests that this dinucleotide is important for normal RNA splicing, and that other variants at these positions may also be clinically significant. Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site, but this prediction has not been confirmed by published transcriptional studies. This variant has been observed in an individual affected with hereditary hemorrhagic telangiectasia (Invitae). This variant is not present in population databases (ExAC no frequency). This sequence change affects an acceptor splice site in intron 7 of the ENG gene. It is expected to disrupt RNA splicing and likely results in an absent or disrupted protein product.
NIHR Bioresource Rare Diseases, University of Cambridge RCV001263085 SCV001441167 pathogenic Telangiectasia, hereditary hemorrhagic, type 1 2018-01-01 criteria provided, single submitter research PVS1+PM2+PP4
GeneDx RCV001664441 SCV001875358 pathogenic not provided 2021-02-12 criteria provided, single submitter clinical testing Has not been previously published as pathogenic or benign to our knowledge; Not observed in large population cohorts (Lek et al., 2016); Canonical splice site variant predicted to result in a null allele in a gene for which loss-of-function is a known mechanism of disease; Reported in ClinVar as a pathogenic variant (ClinVar Variant ID# 663310; Landrum et al., 2016)
Mayo Clinic Laboratories, Mayo Clinic RCV001664441 SCV002103223 pathogenic not provided 2021-06-30 criteria provided, single submitter clinical testing PVS1, PM2, PP4

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