ClinVar Genomic variation as it relates to human health

This variant disrupts the p.Pro449 amino acid residue in ACVRL1. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 20414677; Invitae). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. For these reasons, this variant has been classified as Pathogenic. Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is expected to disrupt ACVRL1 protein function. This sequence change replaces proline, which is neutral and non-polar, with leucine, which is neutral and non-polar, at codon 449 of the ACVRL1 protein (p.Pro449Leu). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individuals with hereditary hemorrhagic telangiectasia (PMID: 16542389; Invitae). ClinVar contains an entry for this variant (Variation ID: 1509552).

The ACVRL1 c.1346C>T; p.Pro449Leu variant is reported in the literature in individuals with HHT (Kim 2019, Sadick 2009, Wehner 2006), and is also reported in ClinVar (Variation ID: 1509552). This variant is absent from the Genome Aggregation Database, indicating it is not a common polymorphism. Computational analyses are uncertain whether this variant is neutral or deleterious (REVEL: 0.677). Based on available information, this variant is considered to be likely pathogenic. References: Kim D et al. Current Status of Clinical Diagnosis and Genetic Analysis of Hereditary Hemorrhagic Telangiectasia in South Korea: Multicenter Case Series and a Systematic Review. Neurointervention. 2019 Sep;14(2):91-98. PMID: 31455059. Sadick H et al. Mutation analysis of "Endoglin" and "Activin receptor-like kinase" genes in German patients with hereditary hemorrhagic telangiectasia and the value of rapid genotyping using an allele-specific PCR-technique. BMC Med Genet. 2009 Jun 9;10:53. PMID: 19508727. Wehner LE et al. Mutation analysis in hereditary haemorrhagic telangiectasia in Germany reveals 11 novel ENG and 12 novel ACVRL1/ALK1 mutations. Clin Genet. 2006 Mar;69(3):239-45. PMID: 16542389.

This sequence change is predicted to replace proline with leucine at codon 449 of the ACVRL1 protein, p.(Pro449Leu). The proline residue is highly conserved (100 vertebrates, UCSC), and is located within the protein tyrosine kinase domain. There is a moderate physicochemical difference between proline and leucine. The variant is absent in a large population cohort (gnomAD v2.1). The variant has been identified in at least six individuals with hereditary haemorrhagic telangiectasia (HHT), two with a clinical diagnosis (PMID: 16542389, 19508727, 31455059; Royal Melbourne Hospital; ClinVar: SCV002300725.1). Multiple lines of computational evidence predict a deleterious effect for the missense substitution (5/7 algorithms). Two different missense changes at the same amino acid position (p.Pro449Ser, p.Pro449Thr) have each been reported in cases with HHT (PMID: 18673552, 20414677). Based on the classification scheme RMH ACMG Guidelines v1.5.1, this variant is classified as LIKELY PATHOGENIC. Following criteria are met: PS4, PM2_Supporting, PP3.

The p.P449L variant (also known as c.1346C>T), located in coding exon 8 of the ACVRL1 gene, results from a C to T substitution at nucleotide position 1346. The proline at codon 449 is replaced by leucine, an amino acid with similar properties. This variant has been reported in multiple individuals with a definite or suspected diagnosis of hereditary hemorrhagic telangiectasia (Wehner LE et al. Clin. Genet., 2006 Mar;69:239-45; Sadick H et al. BMC Med. Genet., 2009 Jun;10:53; Kim D et al. Neurointervention, 2019 Sep;14:91-98). This variant was not reported in population-based cohorts in the Genome Aggregation Database (gnomAD). Based on internal structural analysis, this variant is more disruptive to the protein kinase domain of ACVRL1 than other pathogenic variants in the same domain (Kerr G et al. Angiogenesis, 2015 Apr;18:209-17; Modi V et al. Sci Rep, 2019 12;9:19790). Based on the majority of available evidence to date, this variant is likely to be pathogenic.

PM1, PM2, PS4

The ACVRL1 c.1346C>T variant is predicted to result in the amino acid substitution p.Pro449Leu. This variant has been reported in individuals with hereditary hemorrhagic telangiectasia (HHT) (Wehner et al. 2006. PubMed ID: 16542389; Kim et al. 2019. PubMed ID: 31455059). This variant has not been reported in a large population database, indicating this variant is rare. Other variants impacting the same amino acid (Pro449Thr, Pro449Ala, and Pro449Ser) have been documented in patients with ACVRL1-related disease (Fontalba et al. 2008. PubMed ID: 18673552; Kitayama et al. 2021. PubMed ID: 34872578; Richards-Yutz et al. 2010. PubMed ID: 20414677). Based on this evidence, we interpret the c.1346C>T (p.Pro449Leu) variant as pathogenic.

Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 16542389, 19508727, 31455059)