ClinVar Miner

Submissions for variant NM_001114753.3(ENG):c.68-1G>A

dbSNP: rs878853659
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Total submissions: 4
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000578937 SCV000680677 pathogenic not provided 2023-09-08 criteria provided, single submitter clinical testing Not observed at significant frequency in large population cohorts (gnomAD); 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; This variant is associated with the following publications: (PMID: 25525159, 16752392, 15024723)
Fulgent Genetics, Fulgent Genetics RCV000232191 SCV000893795 likely pathogenic Telangiectasia, hereditary hemorrhagic, type 1 2018-10-31 criteria provided, single submitter clinical testing
Labcorp Genetics (formerly Invitae), Labcorp RCV001388235 SCV001589143 pathogenic Hereditary hemorrhagic telangiectasia 2016-03-17 criteria provided, single submitter clinical testing This sequence change affects an acceptor splice site in intron 1 of the ENG gene. It is expected to disrupt mRNA splicing and likely results in an absent or disrupted protein product. Truncating variants in ENG are known to be pathogenic (PMID: 21158752, 12673790). This particular variant has been identified in a patient with confirmed hereditary hemorrhagic telangiectasia (PMID: 15024723). For these reasons, this variant has been classified as Pathogenic.
Ambry Genetics RCV002365173 SCV002664727 pathogenic Cardiovascular phenotype 2021-04-12 criteria provided, single submitter clinical testing The c.68-1G>A intronic pathogenic mutation results from a G to A substitution one nucleotide upstream from coding exon 2 of the ENG gene. Alterations that disrupt the canonical splice site are expected to result in aberrant splicing. In silico splice site analysis predicts that this alteration will weaken the native splice acceptor site and may result in the creation or strengthening of a novel splice acceptor site. The stop codon in the predicted resulting transcript occurs within the first 150 nucleotides ofthe ENG gene. As such, this alteration may escape nonsense-mediated mRNAdecay and/or be prone to rescue by reinitiation (Rivas et al. Science. 2015 May 8;348(6235):666-9; Lindeboom et al. Nat Genet. 2016 Oct;48(10):1112-8; Rhee et al. Sci Rep. 2017 May 10;7(1):1653). The exact functional effect of this alteration is unknown; however, the impacted region is critical for protein function (Ambry internal data). This alteration has been observed in individuals with personal and family histories of hereditary hemorrhagic telangiectasia (HHT) (Ambry internal data; Lesca G et al. Hum Mutat, 2004 Apr;23:289-99). Based on the supporting evidence, this alteration is interpreted as a disease-causing mutation.

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