Total submissions: 6
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| Invitae | RCV000707407 | SCV000836505 | pathogenic | Hereditary hemorrhagic telangiectasia | 2023-12-16 | criteria provided, single submitter | clinical testing | This sequence change replaces arginine, which is basic and polar, with cysteine, which is neutral and slightly polar, at codon 529 of the ENG protein (p.Arg529Cys). This variant is present in population databases (rs745316066, gnomAD 0.003%). This missense change has been observed in individuals with clinical features of hereditary hemorrhagic telangiectasia (PMID: 21158752; Invitae). ClinVar contains an entry for this variant (Variation ID: 583144). 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%. Experimental studies have shown that this missense change affects ENG function (PMID: 25312062). This variant disrupts the p.Arg529 amino acid residue in ENG. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 16752392, 17384219, 18495117, 22991266). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. For these reasons, this variant has been classified as Pathogenic. |
| ARUP Laboratories, |
RCV001000404 | SCV001157198 | uncertain significance | Telangiectasia, hereditary hemorrhagic, 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. |
| Genetic Services Laboratory, |
RCV001816740 | SCV002067532 | uncertain significance | not specified | 2020-09-14 | criteria provided, single submitter | clinical testing | DNA sequence analysis of the ENG gene demonstrated a sequence change, c.1585C>T, in exon 12 that results in an amino acid change, p.Arg529Cys. This sequence change has been previously described in an individual with multiple pulmonary arteriovenous malformation (AVMs) and epistaxis in conjunction with an exon 4 deletion in the ACVRL1 gene (PMID: 21158752). Family members were unavailable for clinical evaluation or co-segregation study. This variant showed partial cellular surface localization, induced partial BMP9 binding and partial BMP9 response (~ 60% of the wildtype) (PMID: 25312062). This sequence change has been described in three heterozygous individuals in the gnomAD database which corresponds to the overall low population frequency of 0.0011% (dbSNP rs745316066). The p.Arg529Cys change affects a highly conserved amino acid residue located in a domain of the ENG protein that is known to be functional. The p.Arg529Cys substitution appears to be deleterious using several in-silico pathogenicity prediction tools (SIFT, PolyPhen2, Align GVGD, REVEL). Due to these evidences and the lack of functional studies, the clinical significance of the p.Arg529Cys change remains unknown at this time. |
| Gene |
RCV001840729 | SCV002099753 | uncertain significance | not provided | 2021-08-30 | criteria provided, single submitter | clinical testing | Identified in patients with features of hereditary hemorrhagic telangiectasia (HHT), including one patient who harbored another potentially disease-causing variant in the ACVRL1 gene (McDonald et al., 2011; Mallet et al., 2015); Not observed at significant frequency in large population cohorts (gnomAD); Published functional studies suggest a damaging effect as this variant may have an impact on cell surface localization (Mallet et al., 2015); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Reported in ClinVar as a variant of uncertain significance (ClinVar Variant ID# 583144; ClinVar); This variant is associated with the following publications: (PMID: 28564608, 30763665, 31727138, 25312062, 21158752) |
| Mayo Clinic Laboratories, |
RCV001840729 | SCV002541017 | uncertain significance | not provided | 2021-05-20 | criteria provided, single submitter | clinical testing | |
| Ambry Genetics | RCV002397490 | SCV002705976 | uncertain significance | Cardiovascular phenotype | 2023-07-28 | criteria provided, single submitter | clinical testing | The p.R529C variant (also known as c.1585C>T), located in coding exon 12 of the ENG gene, results from a C to T substitution at nucleotide position 1585. The arginine at codon 529 is replaced by cysteine, an amino acid with highly dissimilar properties. In one study, this variant was detected in an individual with multiple pulmonary arteriovenous malformations and epistaxis who also carried a single exon deletion in the ACVRL1 gene (McDonald J et al. Clin. Genet., 2011 Apr;79:335-44). This variant has also been detected in a pulmonary arterial hypertension cohort (Zhu N et al. Genome Med. 2019 11;11(1):69). In a functional study, the protein with this alteration showed approximately 60% surface expression level compared to wild type and approximately 70% of the BMP9-induced luciferase activity; however, the authors comment that the reduced BMP9 response could be the result of the reduced ENG expression in the in vitro system rather than activity changes (Mallet C et al. Hum. Mol. Genet., 2015 Feb;24:1142-54). A disease-causing mutation at the same codon, p.R529H (c.1586G>A), has been described in individuals meeting clinical diagnostic criteria for hereditary hemorrhagic telangiectasia (Bossler AD et al. Hum. Mutat., 2006 Jul;27:667-75). This amino acid position is well conserved in available vertebrate species. In addition, the in silico prediction for this alteration is inconclusive. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear. |