ClinVar Miner

Submissions for variant NM_000118.3(ENG):c.1080_1083del (p.Thr361fs) (rs863223540)

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Total submissions: 4
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000200429 SCV000250087 pathogenic not provided 2018-07-24 criteria provided, single submitter clinical testing The c.1080_1083delGACA pathogenic variant in the ENG gene, also reported as c.1078_1081delGACA due to alternate nomenclature, has been identified previously in multiple members of a large family with HHT (Gallione et al., 1998). It has also been identified in several other unrelated individuals with HHT (Wehner et al., 2006; Bossler wt al., 2006; Olivieri et al., 2007; Nishida et al., 2012). Additionally, the c.1080_1083delGACA variant has not been observed in large population cohorts (Lek et al., 2016). The c.1080_1083delGACA variant causes a shift in reading frame starting at codon threonine 361, changing it to a serine, and creating a premature stop codon at position 7 of the new reading frame, denoted p.Thr361SerfsX7. This pathogenic variant is expected to result in either an abnormal, truncated protein product or loss of protein from this allele through nonsense-mediated mRNA decay. Furthermore, other frameshift variants in the ENG gene have been reported in Human Gene Mutation Database in association with HHT (Stenson et al., 2014), indicating that loss of function is a mechanism of disease for this gene.
Invitae RCV000234034 SCV000283521 pathogenic Hereditary hemorrhagic telangiectasia type 1 2017-04-08 criteria provided, single submitter clinical testing This sequence change deletes 4 nucleotide from exon 8 of the ENG mRNA (c.1080_1083delGACA), causing a frameshift at codon 361. This creates a premature translational stop signal (p.Thr361Serfs*7) and is expected to result in an absent or disrupted protein product. Loss-of-function variants in ENG are known to be pathogenic. This particular truncation has been reported in the literature in multiple individuals affected with hereditary hemorrhagic telangiectasia (PMID: 9554745, 22991266, 16542389, 17786384, 21158752). For these reasons, this variant has been classified as Pathogenic.
NIHR Bioresource Rare Diseases, University of Cambridge RCV000234034 SCV001439428 pathogenic Hereditary hemorrhagic telangiectasia type 1 2018-01-01 criteria provided, single submitter research PVS1+PM2+PP4
Mayo Clinic Laboratories, Mayo Clinic RCV000200429 SCV001713507 pathogenic not provided 2020-06-24 criteria provided, single submitter clinical testing PVS1, PS4, PP1_Strong, PM2, PP4

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