Total submissions: 3
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| Invitae | RCV001386902 | SCV001587301 | pathogenic | Telangiectasia, hereditary hemorrhagic, type 2 | 2022-05-06 | criteria provided, single submitter | clinical testing | This sequence change creates a premature translational stop signal (p.Leu138Glyfs*30) in the ACVRL1 gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in ACVRL1 are known to be pathogenic (PMID: 15879500). This variant is not present in population databases (gnomAD no frequency). This variant has not been reported in the literature in individuals affected with ACVRL1-related conditions. ClinVar contains an entry for this variant (Variation ID: 1073797). For these reasons, this variant has been classified as Pathogenic. |
| ARUP Laboratories, |
RCV001386902 | SCV002049516 | pathogenic | Telangiectasia, hereditary hemorrhagic, type 2 | 2021-09-17 | criteria provided, single submitter | clinical testing | The ACVRL1 c.412_413delCT; p.Leu138GlyfsTer30 variant, to our knowledge, is not reported in the medical literature but is reported in ClinVar (Variation ID: 1073797). This variant is absent from the Genome Aggregation Database, indicating it is not a common polymorphism. This variant causes a frameshift by deleting 2 nucleotides, so it is predicted to result in a truncated protein or mRNA subject to nonsense-mediated decay. Additionally, several downstream truncating variants have been described in individuals with hereditary hemorrhagic telangiectasia (HHT) and are considered pathogenic (Abdalla 2003, McDonald 2011, Komiyama 2014, McDonald 2020). Based on available information, this variant is considered to be pathogenic. References: Abdalla SA et al. Disease-associated mutations in conserved residues of ALK-1 kinase domain. Eur J Hum Genet. 2003 Apr;11(4):279-87. PMID: 12700602. Komiyama M et al. Hereditary hemorrhagic telangiectasia in Japanese patients. J Hum Genet. 2014 Jan;59(1):37-41. PMID: 24196379. McDonald J et al. Molecular diagnosis in hereditary hemorrhagic telangiectasia: findings in a series tested simultaneously by sequencing and deletion/duplication analysis. Clin Genet. 2011 Apr;79(4):335-44. PMID: 21158752. McDonald J et al. Curaçao diagnostic criteria for hereditary hemorrhagic telangiectasia is highly predictive of a pathogenic variant in ENG or ACVRL1 (HHT1 and HHT2). Genet Med. 2020 Jul;22(7):1201-1205. PMID: 32300199. |
| Ambry Genetics | RCV002322366 | SCV002627149 | pathogenic | Cardiovascular phenotype | 2017-03-07 | criteria provided, single submitter | clinical testing | The c.412_413delCT pathogenic mutation, located in coding exon 3 of the ACVRL1 gene, results from a deletion of two nucleotides at nucleotide positions 412 to 413, causing a translational frameshift with a predicted alternate stop codon (p.L138Gfs*30). This alteration is expected to result in loss of function by premature protein truncation or nonsense-mediated mRNA decay. As such, this alteration is interpreted as a disease-causing mutation. This nucleotide position is not well conserved in available vertebrate species. |