Total submissions: 2
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| Ambry Genetics | RCV002442324 | SCV002746397 | uncertain significance | Cardiovascular phenotype | 2016-04-15 | criteria provided, single submitter | clinical testing | The p.Y375N variant (also known as c.1123T>A), located in coding exon 7 of the ACVRL1 gene, results from a T to A substitution at nucleotide position 1123. The tyrosine at codon 375 is replaced by asparagine, an amino acid with dissimilar properties. An alteration at the same codon (p.Y375H) has been reported in an HHT family (Abdalla SA, Eur. J. Hum. Genet. 2003 Apr; 11(4):279-87). This variant was not reported in population based cohorts in the following databases: Database of Single Nucleotide Polymorphisms (dbSNP), NHLBI Exome Sequencing Project (ESP), and 1000 Genomes Project. In the ESP, this variant was not observed in 6503 samples (13006 alleles) with coverage at this position. This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this variant remains unclear. |
| Labcorp Genetics |
RCV005098375 | SCV005734114 | pathogenic | Telangiectasia, hereditary hemorrhagic, type 2 | 2024-04-03 | criteria provided, single submitter | clinical testing | This sequence change replaces tyrosine, which is neutral and polar, with asparagine, which is neutral and polar, at codon 375 of the ACVRL1 protein (p.Tyr375Asn). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with hereditary hemorrhagic telangiectasia (Invitae). ClinVar contains an entry for this variant (Variation ID: 1798510). 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.Tyr375 amino acid residue in ACVRL1. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 12843319, 23919827; Invitae). 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. |