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
GeneDx RCV000755259 SCV000250085 uncertain significance not provided 2020-01-22 criteria provided, single submitter clinical testing Not observed at a significant frequency in large population cohorts (Lek et al., 2016); In silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect; This variant is associated with the following publications: (PMID: 22991266, 17384219, 16752392, 18495117, 21158752, 20414677, 32300199)
Invitae RCV000791433 SCV000283528 likely pathogenic Hereditary hemorrhagic telangiectasia 2020-08-05 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 observed in individuals and families affected with hereditary hemorrhagic telangiectasia (PMID: 17384219, 18495117, 16752392, 22991266, Invitae). 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, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic.
Center of Genomic medicine, Geneva,University Hospital of Geneva RCV000229345 SCV000590887 likely pathogenic Hereditary hemorrhagic telangiectasia type 1 2017-05-16 criteria provided, single submitter clinical testing
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.

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