Total submissions: 4
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| ARUP Laboratories, |
RCV001000141 | SCV001156624 | pathogenic | Telangiectasia, hereditary hemorrhagic, type 2 | 2018-08-08 | criteria provided, single submitter | clinical testing | The ACVRL1 c.1246G>A; p.Gly416Ser variant is reported in the literature in individuals with HHT and has been reported to co-segregate with disease (Argyriou 2006, Lesca 2006, McDonald 2011). This variant is absent from general population databases (1000 Genomes Project, Exome Variant Server, and Genome Aggregation Database), indicating it is not a common polymorphism. The glycine at codon 416 is highly conserved and computational analyses (SIFT, PolyPhen-2) predict this variant to be deleterious. Additionally, this variant occurs in the last nucleotide of the exon and is predicted to impact splicing by significantly weakening the nearby canonical donor splice site (Alamut v.2.11). Based on available information, this variant is considered to be pathogenic. REFERENCES Argyriou L et al. Novel mutations in the ENG and ACVRL1 genes causing hereditary hemorrhagic teleangiectasia. Int J Mol Med. 2006 Apr;17(4):655-9. Lesca G et al. Distribution of ENG and ACVRL1 (ALK1) mutations in French HHT patients. Hum Mutat. 2006 Jun;27(6):598. 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. |
| Mayo Clinic Laboratories, |
RCV001843955 | SCV002103248 | likely pathogenic | not provided | 2021-11-19 | criteria provided, single submitter | clinical testing | PP1, PP3, PP4, PP5, PM2_supporting, PS4_moderate |
| Labcorp Genetics |
RCV001000141 | SCV002243321 | pathogenic | Telangiectasia, hereditary hemorrhagic, type 2 | 2022-11-24 | criteria provided, single submitter | clinical testing | ClinVar contains an entry for this variant (Variation ID: 810860). For these reasons, this variant has been classified as Pathogenic. 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 create or strengthen a splice site. 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. This missense change has been observed in individual(s) with clinical features of ACVRL1-related conditions and/or hereditary hemorrhagic telangiectasia (PMID: 16525724, 16705692, 21158752; Invitae). In at least one individual the variant was observed to be de novo. This variant is not present in population databases (gnomAD no frequency). This sequence change replaces glycine, which is neutral and non-polar, with serine, which is neutral and polar, at codon 416 of the ACVRL1 protein (p.Gly416Ser). This variant also falls at the last nucleotide of exon 8, which is part of the consensus splice site for this exon. |
| Ambry Genetics | RCV002391069 | SCV002668678 | likely pathogenic | Cardiovascular phenotype | 2014-09-25 | criteria provided, single submitter | clinical testing | The p.G416S variant (also known as c.1246G>A) located in coding exon 7 of the ACVRL1 gene. This variant results from a G to A substitution at nucleotide position 1246. The amino acid change results in glycine to serine at codon 416, an amino acid with similar properties. In addition, this change occurs in the last base pair of exon 8 which makes it likely to have some effect on normal mRNA splicing. This alteration was detected in an individual reported with hepatic and pulmonary atrioventricular malformations and family history of hereditary hemorrhagic telangiectasia (Argyriou L et al. Int. J. Mol. Med. 2006; 17:655-9). A further study reported this mutation was found in 2 individuals in the same family who were both affected with HHT (Lesca G et al. Hum. Mutat. 2006; 27:598). This variant was further detected in an individual presenting with epistaxis and telangiectasias (McDonald J et al. Clin. Genet. 2011; 79:335-44). This variant was not reported in population based cohorts in the following databases: Database of Single Nucleotide Polymorphisms (dbSNP), NHLBI Exome Sequencing Project (ESP), and 1000 Genomes Project. This amino acid position is conserved on sequence alignment. Based on two different splice site prediction tools, this alteration is expected to be deleterious to the native splice donor site; however, direct evidence is unavailable. 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. |