Total submissions: 2
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| Labcorp Genetics |
RCV000807692 | SCV000947758 | pathogenic | Telangiectasia, hereditary hemorrhagic, type 2 | 2024-05-22 | criteria provided, single submitter | clinical testing | This sequence change replaces cysteine, which is neutral and slightly polar, with phenylalanine, which is neutral and non-polar, at codon 90 of the ACVRL1 protein (p.Cys90Phe). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individuals with hereditary hemorrhagic telangiectasia (Invitae). ClinVar contains an entry for this variant (Variation ID: 652184). 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 affects a cysteine residue located within the ACVRL1 protein ectodomain. Cysteine residues in this domain of ACVRL1 are involved in the formation of disulfide bridges critical for protein structure and stability (PMID: 22028876, 22718755, 22799562). In addition, missense substitutions within the ACVRL1 ectodomain affecting cysteine residues are overrepresented in patients with HHT (PMID: 20501893, 26176610 and www.hhtmutation.org). This variant disrupts the p.Cys90 amino acid residue in ACVRL1. Other variant(s) that disrupt this residue have been observed in individuals with ACVRL1-related conditions (PMID: 16705692, 24196379), which suggests that this may be a clinically significant amino acid residue. For these reasons, this variant has been classified as Pathogenic. |
| Ambry Genetics | RCV002424882 | SCV002743479 | pathogenic | Cardiovascular phenotype | 2020-10-05 | criteria provided, single submitter | clinical testing | The p.C90F pathogenic mutation (also known as c.269G>T), located in coding exon 2 of the ACVRL1 gene, results from a G to T substitution at nucleotide position 269. The cysteine at codon 90 is replaced by phenylalanine, an amino acid with highly dissimilar properties. This alteration was identified in two individuals in one family; however, specific phenotype information was not provided (Goulielmos GN et al. IJNTR, 2016 Feb;2(1):32-6). Based on internal structural analysis, C90F disrupts a structurally important disulfide bond at a position with internal pathogenic variants (Townson SA et al. J. Biol. Chem., 2012 Aug;287:27313-25). Two other alterations at the same codon, p.C90Y (c.269G>A) and p.C90W (c.270C>G), have been described in individuals with suspected or confirmed hereditary hemorrhagic telangiectasia (Lesca G et al. Hum. Mutat., 2006 Jun;27:598; Gedge F et al. J Mol Diagn, 2007 Apr;9:258-65; Komiyama M et al. J. Hum. Genet., 2014 Jan;59:37-41). This variant was not reported in population-based cohorts in the Genome Aggregation Database (gnomAD). 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 supporting evidence, this alteration is interpreted as a disease-causing mutation. |