ClinVar Miner

Submissions for variant NM_001114753.3(ENG):c.1586G>A (p.Arg529His)

dbSNP: rs863223538
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Total submissions: 7
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000755259 SCV000250085 uncertain significance not provided 2023-09-28 criteria provided, single submitter clinical testing Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 22991266, 17384219, 21158752, 20414677, 16752392, 18495117, 32300199)
Invitae RCV000791433 SCV000283528 pathogenic Hereditary hemorrhagic telangiectasia 2023-11-11 criteria provided, single submitter clinical testing This sequence change replaces arginine, which is basic and polar, with histidine, which is basic and polar, at codon 529 of the ENG protein (p.Arg529His). This variant is present in population databases (no rsID available, gnomAD 0.007%). This missense change has been observed in individuals with hereditary hemorrhagic telangiectasia (PMID: 16752392, 17384219, 18495117, 22991266; Invitae). ClinVar contains an entry for this variant (Variation ID: 213212). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is expected to disrupt ENG protein function with a positive predictive value of 95%. This variant disrupts the p.Arg529 amino acid residue in ENG. Other variant(s) that disrupt this residue have been observed in individuals with ENG-related conditions (PMID: 20414677), which suggests that this may be a clinically significant amino acid residue. For these reasons, this variant has been classified as Pathogenic.
Center of Genomic medicine, Geneva, University Hospital of Geneva RCV000229345 SCV000590887 likely pathogenic Telangiectasia, hereditary hemorrhagic, 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.
Ambry Genetics RCV002399723 SCV002708330 pathogenic Cardiovascular phenotype 2019-01-25 criteria provided, single submitter clinical testing The p.R529H pathogenic mutation (also known as c.1586G>A), located in coding exon 12 of the ENG gene, results from a G to A substitution at nucleotide position 1586. The arginine at codon 529 is replaced by histidine, an amino acid with highly similar properties. This mutation has been observed in multiple individuals with a clinical diagnosis of hereditary hemorrhagic telangiectasia, including four affected individuals in one family (Bossler AD et al. Hum. Mutat., 2006 Jul;27:667-75; Bayrak-Toydemir P et al. Exp. Mol. Pathol., 2008 Aug;85:45-9). Based on the supporting evidence, this alteration is interpreted as a disease-causing mutation.
Greenwood Genetic Center Diagnostic Laboratories, Greenwood Genetic Center RCV000229345 SCV003799021 likely pathogenic Telangiectasia, hereditary hemorrhagic, type 1 2022-12-09 criteria provided, single submitter clinical testing PS3, PM1, PM2
PreventionGenetics, part of Exact Sciences RCV003907720 SCV004727139 likely pathogenic ENG-related disorder 2024-01-31 criteria provided, single submitter clinical testing The ENG c.1586G>A variant is predicted to result in the amino acid substitution p.Arg529His. This variant has been reported in patients with hereditary hemorrhagic telangiectasia in at least two unrelated families (Bossler et al. 2006. PubMed ID: 16752392; Gedge et al. 2007. PubMed ID: 17384219; Supplemental Table, Nishida et al. 2012. PubMed ID: 22991266). This variant is reported in 0.0062% of alleles in individuals of African descent in gnomAD. This variant is interpreted as likely pathogenic.

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