ClinVar Miner

Submissions for variant NM_000118.3(ENG):c.1586G>A (p.Arg529His) (rs863223538)

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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 RCV000755259 SCV000603461 pathogenic not provided 2018-03-23 criteria provided, single submitter clinical testing The ENG c.1586G>A; p.Arg529His variant (rs863223538) has been reported in the literature in individuals with symptoms of HHT (Bossler 2006, Gedge 2007, Nishida 2012). The variant is listed in the ClinVar database (Variation ID: 213212). The variant is reported at a low allele frequency (1 out of 246166 alleles) in the Genome Aggregation Database, indicating it is not a common polymorphism. The arginine at codon 529 is well conserved across species and computational algorithms predict this variant to be damaging to the protein (SIFT, PolyPhen2). Given the above information, this variant is classified as pathogenic. References: Bossler AD et al. Novel mutations in ENG and ACVRL1 identified in a series of 200 individuals undergoing clinical genetic testing for hereditary hemorrhagic telangiectasia (HHT): correlation of genotype with phenotype. Hum Mutat. 2006 27(7):667-75. Gedge F et al. Clinical and analytical sensitivities in hereditary hemorrhagic telangiectasia testing and a report of de novo mutations. J Mol Diagn.2007 9(2):258-65. Nishida T et al. Brain arteriovenous malformations associated with hereditary hemorrhagic telangiectasia: gene-phenotype correlations. Am J Med Genet A. 2012 158A(11):2829-34.
Center of Genomic medicine, Geneva,University Hospital of Geneva RCV000229345 SCV000590887 likely pathogenic Osler hemorrhagic telangiectasia syndrome 2017-05-16 criteria provided, single submitter clinical testing
GeneDx RCV000755259 SCV000250085 uncertain significance not provided 2018-03-23 criteria provided, single submitter clinical testing The R529H variant in the ENG gene has been reported multiple times in association with HHT (Bossler et al., 2006; Gedge et al., 2007; Bayrak-Toydemir et al., 2008; Richards-Yutz et al., 2010; Nishida et al., 2012). Bossler et al. (2006) originally reported R529H in a mother-daughter pair, as well as in an unrelated proband; both families had clinical characteristics of HHT. Bayrak-Toydemir et al. (2008) demonstrated that the R529H variant segregated with HHT phenotype in four affected relatives within the same family. The R529H variant is not observed in large population cohorts (Lek et al., 2016; 1000 Genomes Consortium et al., 2015; Exome Variant Server). However, R529H is a conservative amino acid substitution, which is not likely to impact secondary protein structure as these residues share similar properties. Although this substitution occurs at a position that is conserved in mammals, in silico analysis is inconsistent in its predictions as to whether or not the variant is damaging to the protein structure/function. Furthermore, no definitively pathogenic missense variants in the same or nearby residues have been reported in the Human Gene Mutation Database in association with HHT (Stenson et al., 2014).
Invitae RCV000791433 SCV000283528 likely pathogenic Hereditary hemorrhagic telangiectasia 2018-11-28 criteria provided, single submitter clinical testing This sequence change replaces arginine with histidine at codon 529 of the ENG protein (p.Arg529His). The arginine residue is highly conserved and there is a small physicochemical difference between arginine and histidine. This variant is not present in population databases (ExAC no frequency). This variant has been reported to segregate with hereditary hemorrhagic telangiectasia (HHT) in a single family (PMID: 17384219, 18495117). In addition, it has been observed in an individual that was diagnosed with definite HHT, in an individual affected with epistaxis, mucocutaneous telangiectasias and lung arteriovenous malformations (AVM), and in an individual affected with lung AVM and her daughter that presented with epistaxis and mucocutaneous telangiectasia (PMID: 16752392, 22991266). ClinVar contains an entry for this variant (Variation ID: 213212). Algorithms developed to predict the effect of missense changes on protein structure and function do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Probably Damaging"; Align-GVGD: "Class C0"). In summary, this is a rare missense change that has been reported in many individuals affected with HHT. However, in the absence of conclusive segregation data or functional studies, at this time this change has been classified as Likely Pathogenic.

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