Total submissions: 4
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| ARUP Laboratories, |
RCV000755785 | SCV000883357 | uncertain significance | not provided | 2017-06-27 | criteria provided, single submitter | clinical testing | The ACVRL1 c.905T>C; p.Leu302Pro variant has not been reported in the literature or gene-specific databases. However, a different variant at this codon, p.Leu302Arg, has been reported to segregate with disease in a German family with hereditary hemorrhagic telangiectasia (Schulte 2005). The highly conserved leucine at codon 302 is located in the protein kinase domain, and computational algorithms (SIFT, PolyPhen2, MutationTaster) predict the p.Leu302Pro variant to be damaging to the protein. Due to the limited information regarding p.Leu302Pro, its clinical significance is uncertain at this time. REFERENCES Schulte C et al. High frequency of ENG and ALK1/ACVRL1 mutations in German HHT patients. Hum Mutat. 2005 Jun;25(6):595. |
| Labcorp Genetics |
RCV001040697 | SCV001204286 | uncertain significance | Telangiectasia, hereditary hemorrhagic, type 2 | 2019-10-07 | criteria provided, single submitter | clinical testing | This sequence change replaces leucine with proline at codon 302 of the ACVRL1 protein (p.Leu302Pro). The leucine residue is highly conserved and there is a moderate physicochemical difference between leucine and proline. This variant is not present in population databases (ExAC no frequency). This variant has been observed in an individual affected with clinical features of hereditary hemorrhagic telangiectasia (Invitae). Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be disruptive, but these predictions have not been confirmed by published functional studies and their clinical significance is uncertain. This variant disrupts the p.Leu302 amino acid residue in ACVRL1. Other variant(s) that disrupt this residue have been observed in individuals with ACVRL1-related conditions (PMID: 15880681), which suggests that this may be a clinically significant amino acid residue. 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. |
| NIHR Bioresource Rare Diseases, |
RCV001040697 | SCV001439472 | likely pathogenic | Telangiectasia, hereditary hemorrhagic, type 2 | 2018-01-01 | criteria provided, single submitter | research | PM2+PM1+PP4 |
| Ambry Genetics | RCV002370004 | SCV002688512 | likely pathogenic | Cardiovascular phenotype | 2022-11-14 | criteria provided, single submitter | clinical testing | The p.L302P variant (also known as c.905T>C), located in coding exon 6 of the ACVRL1 gene, results from a T to C substitution at nucleotide position 905. The leucine at codon 302 is replaced by proline, an amino acid with similar properties. This variant has been detected in multiple individuals with clinical features of hereditary hemorrhagic telangiectasia in the literature and at other laboratories (Shovlin CL et al. Blood, 2020 10;136:1907-1918). Based on internal structural analysis, L302P is moderately destabilizing to the local structure and more deleterious than nearby likely pathogenic variants (Kerr G et al. Angiogenesis, 2015 Apr;18:209-17). This amino acid position is highly conserved through mammals but not in all 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. |