ClinVar Miner

Submissions for variant NM_000118.3(ENG):c.1689_1699del (p.Glu563Aspfs)

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Total submissions: 2
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Invitae RCV001041801 SCV001205441 pathogenic Hereditary hemorrhagic telangiectasia 2019-09-09 criteria provided, single submitter clinical testing This sequence change results in a premature translational stop signal in the ENG gene (p.Glu563Aspfs*12). While this is not anticipated to result in nonsense mediated decay, it is expected to disrupt the last 63 amino acids of the ENG protein. This variant is not present in population databases (ExAC no frequency). This variant has been observed in several individuals with clinical features of hereditary hemorrhagic telangiectasia (PMID: 10625079, Invitae). This variant is also described as deltaAGTCCATAGGA, FS at 168 in the literature. This variant disrupts the C-terminus of the ENG protein. Other variant(s) that disrupt this region (p.Leu572) have been determined to be pathogenic (PMID: 11440987). This suggests that variants that disrupt this region of the protein are likely to be causative of disease. For these reasons, this variant has been classified as Pathogenic.
ARUP Laboratories, Molecular Genetics and Genomics,ARUP Laboratories RCV001286214 SCV001472746 pathogenic Hereditary hemorrhagic telangiectasia type 1 2020-02-25 criteria provided, single submitter clinical testing The ENG c.1689_1699del; p.Glu563fs variant is reported in the literature in one individual with a clinical diagnosis of hereditary hemorrhagic telangiectasia (HHT) and a reduced endoglin level in activated monocytes (Cymerman 2000). In testing performed at ARUP Laboratories, this variant has also been observed in two brothers with symptoms of HHT. This variant is absent from general population databases (Exome Variant Server, Genome Aggregation Database), indicating it is not a common polymorphism. This variant causes a frameshift by deleting 11 nucleotides, so it is predicted to result in a truncated protein or mRNA subject to nonsense-mediated decay. Based on the available information, this variant is considered to be pathogenic. References: Cymerman et al. Identification of hereditary hemorrhagic telangiectasia type 1 in newborns by protein expression and mutation analysis of endoglin. Pediatr Res. 2000 Jan;47(1):24-35.

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