Total submissions: 3
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| Labcorp Genetics |
RCV000812604 | SCV000952922 | pathogenic | Telangiectasia, hereditary hemorrhagic, type 2 | 2024-04-11 | criteria provided, single submitter | clinical testing | This sequence change replaces cysteine, which is neutral and slightly polar, with arginine, which is basic and polar, at codon 344 of the ACVRL1 protein (p.Cys344Arg). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individuals with hereditary hemorrhagic telangiectasia (HHT) (PMID: 16470787, 16752392, 18673552, 19767588). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 656236). 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 with a positive predictive value of 95%. This variant disrupts the p.Cys344 amino acid residue in ACVRL1. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 10767348, 12114496, 14684682, 15880681, 16540754, 16542389, 17384219). 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. |
| Ambry Genetics | RCV002381809 | SCV002697244 | likely pathogenic | Cardiovascular phenotype | 2022-10-24 | criteria provided, single submitter | clinical testing | The p.C344R variant (also known as c.1030T>C), located in coding exon 6 of the ACVRL1 gene, results from a T to C substitution at nucleotide position 1030. The cysteine at codon 344 is replaced by arginine, an amino acid with highly dissimilar properties. This alteration has been reported in multiple individuals and families with confirmed or suspected HHT (Bossler AD et al. Hum. Mutat., 2006 Jul;27:667-75; Gedge F et al. J Mol Diagn, 2007 Apr;9:258-65; Bayrak-Toydemir P et al. Am. J. Med. Genet. A, 2006 Mar;140:463-70; McDonald J et al. J Mol Diagn, 2009 Nov;11:569-75; Ruiz-Llorente L et al. J Clin Med. 2020 Sep;9(9)), and in a pulmonary arterial hypertension cohort (Gräf S et al. Nat Commun. 2018 04;9(1):1416). This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. Based on the majority of available evidence to date, this variant is likely to be pathogenic. |
| NIHR Bioresource Rare Diseases, |
RCV001003754 | SCV001162197 | pathogenic | Pulmonary arterial hypertension | no assertion criteria provided | research |