Total submissions: 2
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| Invitae | RCV001383045 | SCV001582058 | pathogenic | Telangiectasia, hereditary hemorrhagic, type 2 | 2023-11-27 | criteria provided, single submitter | clinical testing | This sequence change replaces proline, which is neutral and non-polar, with serine, which is neutral and polar, at codon 433 of the ACVRL1 protein (p.Pro433Ser). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with hereditary hemorrhagic telangiectasia (PMID: 15517393, 16123970). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 1070764). 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.Pro433 amino acid residue in ACVRL1. Other variant(s) that disrupt this residue have been observed in individuals with ACVRL1-related conditions (PMID: 16752392, 31594285), which suggests that this may be a clinically significant amino acid residue. For these reasons, this variant has been classified as Pathogenic. |
| Ambry Genetics | RCV002384546 | SCV002691385 | likely pathogenic | Cardiovascular phenotype | 2021-12-01 | criteria provided, single submitter | clinical testing | The p.P433S variant (also known as c.1297C>T), located in coding exon 8 of the ACVRL1 gene, results from a C to T substitution at nucleotide position 1297. The proline at codon 433 is replaced by serine, an amino acid with similar properties. This variant has been detected in individuals reported to have hereditary hemorrhagic telangiectasia (HHT), and was reported to segregate with disease in four affected members of family (Letteboer TG et al. Hum. Genet., 2005 Jan;116:8-16; Argyriou L et al. Liver Transpl., 2005 Sep;11:1132-5; Ambry internal data). This variant is considered to be rare based on population 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 majority of available evidence to date, this variant is likely to be pathogenic. |