ClinVar Miner

Submissions for variant NM_000118.3(ENG):c.1585C>T (p.Arg529Cys) (rs745316066)

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Total submissions: 2
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Invitae RCV000707407 SCV000836505 uncertain significance Hereditary hemorrhagic telangiectasia 2020-08-30 criteria provided, single submitter clinical testing This sequence change replaces arginine with cysteine at codon 529 of the ENG protein (p.Arg529Cys). The arginine residue is moderately conserved and there is a large physicochemical difference between arginine and cysteine. This variant is present in population databases (rs745316066, ExAC 0.003%). This variant has been reported in individuals with clinical features of hereditary hemorrhagic telangiectasia (HHT) or pulmonary arterial hypertension (PMID: 25312062, 21158752, 31727138, Invitae). However, in at least one individual a pathogenic allele was also identified in ACVRL1, which suggests that this c.1585C>T variant was not the primary cause of disease (PMID: 21158752). Experimental studies have shown that this missense change impairs ENG protein function (PMID: 25312062). A different missense substitution at this codon (p.Arg529His) has been determined to be pathogenic (PMID: 16752392, 17384219, 18495117, 22991266). This suggests that the arginine residue is critical for ENG protein function and that other missense substitutions at this position may also be pathogenic. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance.
ARUP Laboratories, Molecular Genetics and Genomics,ARUP Laboratories RCV001000404 SCV001157198 uncertain significance Hereditary hemorrhagic telangiectasia type 1 2018-12-10 criteria provided, single submitter clinical testing The ENG c.1585C>T; p.Arg529Cys variant (rs745316066), is reported in individuals with suspected HHT (Mallet 2015, McDonald 2011), and is reported in ClinVar (Variation ID: 583144). However, in one individual, the deletion of ACVRL1 exon 4 was also identified by multiplex ligation-dependent probe amplification (MLPA) (McDonald 2011). Functional analyses of the p.Arg529Cys variant protein shows partially impaired BMP9 binding and response, as well as partially impaired localization (Mallet 2015). Furthermore, a different variant at this codon, p.Arg529His, is reported in the literature in individuals with symptoms of HHT (Bossler 2006, Gedge 2007, Nishida 2012). The p.Arg529Cys variant is found in the general population with a low allele frequency of 0.001% (3/282678 alleles) in the Genome Aggregation Database. The arginine at codon 529 is highly conserved and computational analyses (SIFT, PolyPhen-2) predict that this variant is deleterious. Due to limited information, the clinical significance of the p.Arg529Cys variant is uncertain at this time. 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. Mallet C et al. Functional analysis of endoglin mutations from hereditary hemorrhagic telangiectasia type 1 patients reveals different mechanisms for endoglin loss of function. Hum Mol Genet. 2015 Feb 15;24(4):1142-54. McDonald J et al. Molecular diagnosis in hereditary hemorrhagic telangiectasia: findings in a series tested simultaneously by sequencing and deletion/duplication analysis. Clin Genet. 2011 Apr;79(4):335-44. 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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