ClinVar Miner

Submissions for variant NM_000118.3(ENG):c.817-1G>C (rs1564455715)

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Total submissions: 2
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Invitae RCV000694887 SCV000823353 pathogenic Hereditary hemorrhagic telangiectasia 2019-02-14 criteria provided, single submitter clinical testing This sequence change affects an acceptor splice site in intron 6 of the ENG gene. It is expected to disrupt RNA splicing and likely results in an absent or disrupted protein product. This variant is not present in population databases (ExAC no frequency). Disruption of this splice site has been observed in individuals affected with hereditary hemorrhagic telangiectasia (HHT) (PMID: 24001356, 25970827, 20824275, Invitae). ClinVar contains an entry for this variant (Variation ID: 573259). 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). For these reasons, this variant has been classified as Pathogenic.
ARUP Laboratories, Molecular Genetics and Genomics,ARUP Laboratories RCV001285575 SCV001472035 pathogenic Hereditary hemorrhagic telangiectasia type 1 2019-07-23 criteria provided, single submitter clinical testing The ENG c.817-1G>C variant is reported in the literature in an individual affected with hereditary hemorrhagic telangiectasia (HHT) (Torring 2014). This variant is absent from general population databases (Exome Variant Server, Genome Aggregation Database), indicating it is not a common polymorphism. This variant abolishes the canonical splice acceptor site of intron 6, which is likely to disrupt gene function. Additionally, another variant at the same nucleotide (c.817-1G>T) has been described in individuals with HHT, supporting the notion that this position is intolerant of variation (Fodstad 2011, Heimdal 2016). Based on available information, the c.817-1G>C variant is considered to be pathogenic. References: Fodstad P et al. Anti-VEGF with 3-week intervals is effective on anemia in a patient with severe hereditary hemorrhagic telangiectasia. Ann Hematol. 2011 May;90(5):611-2. Heimdal K et al. Mutation analysis in Norwegian families with hereditary hemorrhagic telangiectasia: founder mutations in ACVRL1. Clin Genet. 2016 Feb;89(2):182-6. Torring PM et al. National mutation study among Danish patients with hereditary haemorrhagic telangiectasia. Clin Genet. 2014 Aug;86(2):123-33.

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