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

dbSNP: rs863223538

Total submissions: 8

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
ClinGen Hereditary Hemorrhagic Telangiectasia Variant Curation Expert Panel, ClinGen	RCV000229345	SCV005326488	pathogenic	Telangiectasia, hereditary hemorrhagic, type 1	2024-09-11	reviewed by expert panel	curation	The NM_001114753.3: c.1586G>A variant in ENG is a missense variant predicted to cause substitution of arginine by histidine at amino acid 529 (p.Arg529His). This variant has been reported in more than 10 probands with a phenotype consistent with HHT (PS4; PMID: 22991266, 16752392, Internal lab contributors). At least one patient's phenotype meets Curacao Criteria for HHT, and sequencing and large deletion/duplication analysis was performed for ENG and ACVRL1, which is highly specific for HHT (PP4_Moderate; Internal lab contributors). The variant has been reported to segregate with HHT in more than 20 affected family members from multiple families (PP1_Strong; Internal lab contributors). The overall minor allele frequency in gnomAD v2.1.1 is 0.000004 (1/251282 alleles), which is lower than the ClinGen Hereditary Hemorrhagic Telangiectasia VCEP threshold (<6 total alleles) for PM2_Supporting, meeting this criterion (PM2_Supporting). The computational predictor REVEL gives a score of 0.579, which is neither above nor below the thresholds predicting a damaging or benign impact on ENG function. In summary, this variant meets the criteria to be classified as pathogenic for autosomal dominant hereditary hemorrhagic telangiectasia based on the ACMG/AMP criteria applied, as specified by the ClinGen Hereditary Hemorrhagic Telangiectasia Variant Curation Expert Panel: PM2_Supporting, PS4, PP4_Moderate, PP1_Strong (specifications version 1.1.0; 09/11/2024).
GeneDx	RCV000755259	SCV000250085	likely pathogenic	not provided	2024-09-11	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, 32300199, 16752392, 18495117)
Labcorp Genetics (formerly Invitae), Labcorp	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	2024-04-16	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). This amino acid position is well conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. Based on the supporting evidence, this variant 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	no assertion criteria provided	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.