Total submissions: 3
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| Labcorp Genetics |
RCV000707489 | SCV000836589 | pathogenic | Telangiectasia, hereditary hemorrhagic, type 2 | 2024-08-06 | criteria provided, single submitter | clinical testing | This sequence change replaces glycine, which is neutral and non-polar, with arginine, which is basic and polar, at codon 350 of the ACVRL1 protein (p.Gly350Arg). This variant also falls at the last nucleotide of exon 7, which is part of the consensus splice site for this exon. This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with hereditary hemorrhagic telangiectasia (PMID: 15517393, 17384219, 21158752; Invitae). ClinVar contains an entry for this variant (Variation ID: 583213). An algorithm developed to predict the effect of missense changes on protein structure and function (PolyPhen-2) suggests that this variant is likely to be disruptive. Variants that disrupt the consensus splice site are a relatively common cause of aberrant splicing (PMID: 17576681, 9536098). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. For these reasons, this variant has been classified as Pathogenic. |
| Ambry Genetics | RCV002397491 | SCV002709159 | pathogenic | Cardiovascular phenotype | 2024-09-10 | criteria provided, single submitter | clinical testing | The p.G350R pathogenic mutation (also known as c.1048G>C), located in coding exon 6 of the ACVRL1 gene, results from a G to C substitution at nucleotide position 1048. The glycine at codon 350 is replaced by arginine, an amino acid with dissimilar properties. However, this change occurs in the last base pair of coding exon 6, which makes it likely to have some effect on normal mRNA splicing. This alteration has been reported in individuals with a clinical diagnosis of hereditary hemorrhagic telangiectasia (HHT) (Letteboer TG et al. Hum. Genet., 2005 Jan;116:8-16; Gedge F et al. J Mol Diagn, 2007 Apr;9:258-65). This nucleotide position is highly conserved in available vertebrate species. This amino acid position is highly conserved in available vertebrate species. In silico splice site analysis predicts that this alteration will result in the creation or strengthening of a novel splice donor site. In addition, this alteration is predicted to be deleterious by Bayesdel in silico analysis. This variant is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). Based on the supporting evidence, this alteration is interpreted as a disease-causing mutation. |
| ARUP Laboratories, |
RCV000707489 | SCV005879949 | pathogenic | Telangiectasia, hereditary hemorrhagic, type 2 | 2024-11-16 | criteria provided, single submitter | clinical testing | The ACVRL1 c.1048G>C; p.Gly350Arg variant (rs1565594547) is reported in the literature in multiple individuals affected with hereditary hemorrhagic telangiectasia (HHT) (Gedge 2007, Letteboer 2005, McDonald 2011). This variant is reported in ClinVar (Variation ID: 583213) and is absent from the Genome Aggregation Database (v2.1.1), indicating it is not a common polymorphism. Additionally, another variant at this codon (c.1048G>A; p.Gly350Ser) has been reported in individuals with HHT and is considered disease-causing (Schulte 2005). Computational analyses predict that this variant is deleterious (REVEL: 0.975). This is a missense variant occurring at the last nucleotide on exon 6, and computational analyses (Alamut Visual Plus v.1.11) predict that this variant may impact splicing by weakening the nearby canonical donor splice site. Based on available information, this variant is considered to be pathogenic. References: Gedge F et al. Clinical and analytical sensitivities in hereditary hemorrhagic telangiectasia testing and a report of de novo mutations. J Mol Diagn. 2007 Apr;9(2):258-65. PMID: 17384219. Letteboer TG et al. Hereditary hemorrhagic telangiectasia: ENG and ALK-1 mutations in Dutch patients. Hum Genet. 2005 Jan;116(1-2):8-16. PMID: 15517393. 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. Schulte C et al. High frequency of ENG and ALK1/ACVRL1 mutations in German HHT patients. Hum Mutat. 2005 Jun;25(6):595. PMID: 15880681. |