Total submissions: 3
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| Labcorp Genetics |
RCV000552998 | SCV000639394 | pathogenic | Telangiectasia, hereditary hemorrhagic, type 2 | 2021-02-27 | criteria provided, single submitter | clinical testing | This sequence change results in a premature translational stop signal in the ACVRL1 gene (p.Cys471*). While this is not anticipated to result in nonsense mediated decay, it is expected to disrupt the last 33 amino acids of the ACVRL1 protein. This variant is not present in population databases (ExAC no frequency). This variant has been observed in individuals affected with hereditary hemorrhagic telangiectasia (PMID: 16752392, 22991266, 26401274). ClinVar contains an entry for this variant (Variation ID: 464759). This variant disrupts the C-terminus of the ACVRL1 protein. Other variant(s) that disrupt this region (p.Arg479*) have been determined to be pathogenic (PMID: 15024723, 16540754, 23722869). This suggests that variants that disrupt this region of the protein are likely to be causative of disease. For these reasons, this variant has been classified as Pathogenic. |
| Ambry Genetics | RCV002395381 | SCV002700362 | pathogenic | Cardiovascular phenotype | 2017-01-09 | criteria provided, single submitter | clinical testing | The p.C471* pathogenic mutation (also known as c.1413C>A), located in coding exon 9 of the ACVRL1 gene, results from a C to A substitution at nucleotide position 1413. This changes the amino acid from a cysteine to a stop codon within coding exon 9. This mutation was detected in multiple individual with clinical features of hereditary hemorrhagic telangiectasia (HHT), including one individual with epistaxis, telangiectasias, arteriovenous malformations, and a family history of HHT (Bossler AD et al. Hum. Mutat., 2006 Jul;27:667-75; Nishida T et al. Am. J. Med. Genet. A, 2012 Nov;158A:2829-34; Kuchtey RW et al. Clin Case Rep, 2015 Sep;3:725-7). In addition to the clinical data presented in the literature, 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. |
| ARUP Laboratories, |
RCV000552998 | SCV005877838 | pathogenic | Telangiectasia, hereditary hemorrhagic, type 2 | 2024-03-19 | criteria provided, single submitter | clinical testing | The ACVRL1 c.1413C>A; p.Cys471Ter variant (rs1301762186; ClinVar Variation ID: 464759) is reported in the literature in individuals affected with HHT (Bossler 2006, Kuchtey 2015, Nishida 2012). This variant is absent from the Genome Aggregation Database (v2.1.1), indicating it is not a common polymorphism. This variant results in a premature termination codon in the last exon of the ACVRL1 gene. While this may not lead to nonsense-mediated decay, it is expected to create a truncated ACVRL1 protein. Based on available information, this variant is considered to be pathogenic. References: Bossler AD et al. Novel mutations in ENG and ACVRL1 identified in a series of 200 individuals undergoing clinical genetic testing for hereditary hemorrhagic telangiectasia (HHT): correlation of genotype with phenotype. Hum Mutat. 2006 Jul;27(7):667-75. PMID: 16752392. Kuchtey RW et al. Severe open angle glaucoma in hereditary hemorrhagic telangiectasia. Clin Case Rep. 2015 Sep;3(9):725-7. PMID: 26401274. Nishida T et al. Brain arteriovenous malformations associated with hereditary hemorrhagic telangiectasia: gene-phenotype correlations. Am J Med Genet A. 2012 Nov;158A(11):2829-34. PMID: 22991266. |