Total submissions: 2
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| Invitae | RCV001316742 | SCV001507377 | uncertain significance | Telangiectasia, hereditary hemorrhagic, type 2 | 2020-08-06 | criteria provided, single submitter | clinical testing | In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. 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. This sequence change replaces tyrosine with cysteine at codon 88 of the ACVRL1 protein (p.Tyr88Cys). The tyrosine residue is moderately conserved and there is a large physicochemical difference between tyrosine and cysteine. This variant is not present in population databases (ExAC no frequency). This variant has been observed in individual(s) with hereditary hemorrhagic telangiectasia (PMID: 17384219, 23729109, 29923633). |
| Ambry Genetics | RCV002456418 | SCV002740021 | uncertain significance | Cardiovascular phenotype | 2019-04-03 | criteria provided, single submitter | clinical testing | The p.Y88C variant (also known as c.263A>G), located in coding exon 2 of the ACVRL1 gene, results from an A to G substitution at nucleotide position 263. The tyrosine at codon 88 is replaced by cysteine, an amino acid with highly dissimilar properties. This variant was identified in an individual with a clinical diagnosis of hereditary hemorrhagic telangiectasia (HHT); however, specific clinical information was limited (Gedge F et al. J Mol Diagn, 2007 Apr;9:258-65). It was also identified in a Japanese woman with telangiectasias, hepatic arteriovenous malformations, and a family history of HHT (Yaginuma A et al. J. Dermatol., 2019 Jan;46:e22-e24). This amino acid position is not well conserved in available vertebrate species. In addition, this alteration is predicted to be tolerated by in silico analysis. Based on available evidence to date, the clinical significance of this alteration remains unclear. |