Total submissions: 2
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| Labcorp Genetics |
RCV001911102 | SCV002158450 | pathogenic | Telangiectasia, hereditary hemorrhagic, type 2 | 2023-08-30 | criteria provided, single submitter | clinical testing | For these reasons, this variant has been classified as Pathogenic. This variant disrupts the p.Trp399 amino acid residue in ACVRL1. Other variant(s) that disrupt this residue have been observed in individuals with ACVRL1-related conditions (PMID: 14684682, 23919827, 25318803), which suggests that this may be a clinically significant amino acid residue. 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 ACVRL1 protein function. ClinVar contains an entry for this variant (Variation ID: 1391866). This missense change has been observed in individual(s) with clinical features of hereditary hemorrhagic telangiectasia (Invitae). This variant is not present in population databases (gnomAD no frequency). This sequence change replaces tryptophan, which is neutral and slightly polar, with glycine, which is neutral and non-polar, at codon 399 of the ACVRL1 protein (p.Trp399Gly). |
| Ambry Genetics | RCV002334821 | SCV002644322 | pathogenic | Cardiovascular phenotype | 2024-11-27 | criteria provided, single submitter | clinical testing | The p.W399G pathogenic mutation (also known as c.1195T>G), located in coding exon 7 of the ACVRL1 gene, results from a T to G substitution at nucleotide position 1195. The tryptophan at codon 399 is replaced by glycine, an amino acid with highly dissimilar properties. This variant was reported in individual(s) with features consistent with hereditary hemorrhagic telangiectasia (HHT) (Ambry internal data). Other variants at the same codon, p.W399R (c.1195T>C) and p.W399S (c.1196G>C), have been identified in individuals with features consistent with HHT and ACVRL1-related pulmonary arterial hypertension (Chen YJ et al, Eur. J. Clin. Invest. 2013 Oct; 43(10):1016-24; Harrison RE et al, J. Med. Genet. 2003 Dec; 40(12):865-71; Ishiwata T et al, Intern. Med. 2014 ; 53(20):2359-63). This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. This variant is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). Based on the supporting evidence, this variant is interpreted as a disease-causing mutation. |