Total submissions: 3
Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
---|---|---|---|---|---|---|---|---|
NIHR Bioresource Rare Diseases, |
RCV001263079 | SCV001441159 | likely pathogenic | Telangiectasia, hereditary hemorrhagic, type 1 | 2018-01-01 | criteria provided, single submitter | research | PS3+PM2+PP4+PP5 |
Invitae | RCV001880054 | SCV002303014 | pathogenic | Hereditary hemorrhagic telangiectasia | 2023-10-04 | criteria provided, single submitter | clinical testing | This sequence change replaces alanine, which is neutral and non-polar, with aspartic acid, which is acidic and polar, at codon 308 of the ENG protein (p.Ala308Asp). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individuals with clinical features of hereditary hemorrhagic telangiectasia (PMID: 16690726, 16752392, 22991266, 32573726). ClinVar contains an entry for this variant (Variation ID: 983206). 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. Experimental studies have shown that this missense change affects ENG function (PMID: 22022569). For these reasons, this variant has been classified as Pathogenic. |
Ambry Genetics | RCV002375316 | SCV002686804 | pathogenic | Cardiovascular phenotype | 2017-07-11 | criteria provided, single submitter | clinical testing | The p.A308D pathogenic mutation (also known as c.923C>A), located in coding exon 7 of the ENG gene, results from a C to A substitution at nucleotide position 923. The alanine at codon 308 is replaced by aspartic acid, an amino acid with dissimilar properties. This mutation was identified in an individual with hereditary hemorrhagic telangiectasia (HHT) and a brain arteriovenous malformation (Nishida T et al. Am. J. Med. Genet. A, 2012 Nov;158A:2829-34). In two unrelated HHT families, this mutation segregated with disease (Bossler AD et al. Hum. Mutat., 2006 Jul;27:667-75); Prigoda NL et al. J. Med. Genet., 2006 Sep;43:722-8). An in vitro functional study found this mutation resulted in retention and mislocalization of the ENG protein to the endoplasmic reticulum instead of the plamsa membrane (Ali BR et al. PLoS ONE, 2011 Oct;6:e26206). Based on the supporting evidence, this alteration is interpreted as a disease-causing mutation. |