ClinVar Miner

Submissions for variant NM_000118.3(ENG):c.511C>T (p.Arg171Ter) (rs1554810490)

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Total submissions: 4
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
ARUP Laboratories, Molecular Genetics and Genomics,ARUP Laboratories RCV000627219 SCV000603445 pathogenic not provided 2018-02-11 criteria provided, single submitter clinical testing The ENG c.511C>T; p.Arg171Ter variant is reported in the literature in individuals and families affected with hereditary hemorrhagic telangiectasia (Berg 2003, Goldschmidt 2005, Lastella 2003, Lesca 2004, Sanz-Rodriguez 2004, Shovlin 1997). This variant is reported as pathogenic in ClinVar (Variation ID: 439644) and is absent from the general population databases (1000 Genomes Project, Exome Variant Server, Genome Aggregation Database), indicating it is not a common polymorphism. This variant induces an early termination codon and is predicted to result in a truncated protein or mRNA subject to nonsense-mediated decay. In vitro functional analyses demonstrate diminished upregulation of endoglin during monocyte activation (Sanz-Rodriguez 2004). Based on the above information, this variant is considered pathogenic. References: Berg J et al. Hereditary haemorrhagic telangiectasia: a questionnaire based study to delineate the different phenotypes caused by endoglin and ALK1 mutations. J Med Genet. 2003 Aug;40(8):585-90. Goldschmidt N et al. Association of hereditary hemorrhagic telangiectasia and hereditary nonpolyposis colorectal cancer in the same kindred. Int J Cancer. 2005 Sep 20;116(5):808-12. Lastella P et al. Endoglin gene mutations and polymorphisms in Italian patients with hereditary haemorrhagic telangiectasia. Clin Genet. 2003 Jun;63(6):536-40. Lesca G et al. Molecular screening of ALK1/ACVRL1 and ENG genes in hereditary hemorrhagic telangiectasia in France. Hum Mutat. 2004 Apr;23(4):289-99. Sanz-Rodriguez F et al. Mutation analysis in Spanish patients with hereditary hemorrhagic telangiectasia: deficient endoglin up-regulation in activated monocytes. Clin Chem. 2004 Nov;50(11):2003-11. Shovlin C et al. Characterization of endoglin and identification of novel mutations in hereditary hemorrhagic telangiectasia. Am J Hum Genet. 1997 Jul;61(1):68-79.
Invitae RCV000534162 SCV000629572 pathogenic Hereditary hemorrhagic telangiectasia 2018-11-16 criteria provided, single submitter clinical testing This sequence change creates a premature translational stop signal at codon 171 (p.Arg171*) of the ENG gene. It is expected to result in an absent or disrupted protein product. This variant is not present in population databases (ExAC no frequency). Loss-of-function variants in ENG are known to be pathogenic. This particular variant has been reported in the literature in individuals affected with hereditary hemorrhagic telangiectasia (PMID: 15024723, 12920067). This variant has been reported to segregate with hereditary hemorrhagic telangiectasia in several families (PMID: 9245986, 15849752, 15375013). Experimental studies have shown that this nonsense change disrupts mRNA stability and up-regulation of endoglin in activated monocytes (PMID: 15375013, 9245986). For these reasons, this variant has been classified as Pathogenic.
GeneDx RCV000627219 SCV000748207 pathogenic not provided 2018-09-20 criteria provided, single submitter clinical testing The R171X pathogenic variant in the ENG gene has been reported multiple times in association with HHT (Shovlin et al., 1997; Lastella et al., 2003; Lesca et al., 2004; Sanz-Rodriguez et al., 2004; Fernandez-L et al., 2005; Goldschmidt et al., 2005; Fernandez-L et al., 2006; Lee et al., 2011; Brecht et al., 2016). Additionally, R171X has been shown to segregate with HHT phenotype in many affected individuals from unrelated families reported in the published literature (Shovlin et al., 1997; Lastella et al., 2003; Sanz-Rodriguez et al., 2004; Goldschmidt et al., 2005; Lee et al., 2011; Brecht et al., 2016). This variant has also been observed in several individuals referred for HHT genetic testing at GeneDx. R171X is predicted to cause loss of normal protein function either by protein truncation or nonsense-mediated mRNA decay. Experimental studies have demonstrated that the R171X variant results in premature mRNA degradation (Shovlin et al., 1997) and diminishes endoglin up-regulation in activated monocytes (Sanz-Rodriguez et al., 2004). Other nonsense pathogenic variants in the ENG gene have been reported in HGMD in association with HHT (Stenson et al., 2014). Furthermore, the R171X variant is not observed in large population cohorts (Lek et al., 2016).
NIHR Bioresource Rare Diseases, University of Cambridge RCV001263082 SCV001441163 pathogenic Hereditary hemorrhagic telangiectasia type 1 2018-01-01 criteria provided, single submitter research PVS1+PM2+PP4

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