ClinVar Miner

Submissions for variant NM_001114753.3(ENG):c.1311+2T>C

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Total submissions: 2
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Invitae RCV003062234 SCV003441486 pathogenic Hereditary hemorrhagic telangiectasia 2022-05-27 criteria provided, single submitter clinical testing This sequence change affects a donor splice site in intron 10 of the ENG 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 ENG are known to be pathogenic (PMID: 15879500). For these reasons, this variant has been classified as Pathogenic. Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. Disruption of this splice site has been observed in individuals with hereditary hemorrhagic telangiectasia (PMID: 16752392, 21158752). This variant is not present in population databases (gnomAD no frequency).
Molecular Genetics, Royal Melbourne Hospital RCV003062234 SCV004812436 likely pathogenic Hereditary hemorrhagic telangiectasia 2023-03-30 criteria provided, single submitter clinical testing This sequence change in ENG occurs within the canonical splice donor site (+ 2) of intron 10. It is predicted to cause skipping of biologically relevant-exon 10, resulting in an in-frame deletion (removes amino acids 425-437) that is expected to escape nonsense-mediated decay and remove <10% of the protein. The region of the Zona Pellucida domain removed is expected to be critical to protein function because multiple pathogenic variants altering this splice site have been reported (c.1311+2T>A, c.1311+2T>G, c.1311G>C, c.1311G>A; ARUP ENG database; PMID: 9554745, 10625079, 15517393). This variant is absent from the population database gnomAD v2.1 and v3.1. It has been reported in at least two probands with a clinical diagnosis of hereditary haemorrhagic telangiectasia (PMID: 16752392; internal laboratory data). Based on the classification scheme RMH Modified ACMG Guidelines v1.5.1, this variant is classified as LIKELY PATHOGENIC. Following criteria are met: PVS1_Strong, PS4_Moderate, PM2_Supporting.

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