ClinVar Genomic variation as it relates to human health

The NM_000020.3: c.1232G>A variant in ACVRL1 is a missense variant predicted to cause substitution of arginine by glutamine at amino acid 411 (p.Arg411Gln). The overall minor allele frequency in gnomAD v2.1.1 is 0.000007980 (2/250642 alleles), which is lower than the ClinGen Hereditary Hemorrhagic Telangiectasia VCEP threshold (<6 total alleles) for PM2_Supporting, meeting this criterion (PM2_Supporting). This variant has been reported in >10 probands with a phenotype consistent with HHT (PS4; PMID: 8640225, 31400083, 32300199, Internal lab contributors). At least one patient's phenotype meets Curacao Criteria for HHT, and sequencing and large deletion/duplication analysis was performed for ENG and ACVRL1, which is highly specific for HHT (PP4_Moderate; PMID: 32300199). The variant has been reported to segregate with HHT in 8 affected family members from one family (PP1_Strong; PMID: 8640225). The computational predictor REVEL gives a score of 0.904, which is above the threshold of greater than or equal to 0.644, evidence that correlates with impact to ACVRL1 function (PP3). Additionally, binding assays in cell lines showed no BMP9 response indicating that this variant impacts protein function (PS3_Supporting; PMID: 20501893). In summary, this variant meets the criteria to be classified as pathogenic for autosomal dominant hereditary hemorrhagic telangiectasia based on the ACMG/AMP criteria applied, as specified by the ClinGen Hereditary Hemorrhagic Telangiectasia Variant Curation Expert Panel: PS4, PP1_Strong, PP4_Moderate, PM2_Supporting, PP3, PS3_Supporting (specification version 1.0.0; 1/4/2024).

PS3+PM2+PP4+PP5

The ACVRL1 c.1232G>A; p.Arg411Gln variant (rs121909284) has been reported in ClinVar (Variation ID: 8243), and described in the literature in multiple families with hereditary hemorrhagic telangiectasia (HHT) (see HHT database link and references therein). Additionally, this variant has been shown to have defective BMP9 ligand signaling (Ricard 2010). The arginine at codon 411 is a highly conserved residue located in the protein kinase domain, and computational algorithms (SIFT, PolyPhen2, MutationTaster) predict this variant to be damaging to the protein. Taken together, this variant is considered pathogenic. REFERENCES Link to ARUP HHT database: http://arup.utah.edu/database/ACVRL1/ACVRL1_display.php Link to ClinVar for p.Arg411Gln: https://www.ncbi.nlm.nih.gov/clinvar/variation/8243/ Ricard N et al. (2010) Functional analysis of the BMP9 response of ALK1 mutants from HHT2 patients: a diagnostic tool for novel ACVRL1 mutations. Blood. 116(9):1604-12.

Published functional studies demonstrate reduced ACVRL1 activity (Gu et al., 2006; Ricard et al., 2010; Laux et al., 2013); 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: 17384219, 15521985, 16754821, 25892364, 34872578, 20501893, 11802521, 12700602, 14684682, 18673552, 16540754, 16752392, 16470787, 16429404, 16282348, 23863480, 15611116, 20067780, 28652319, 15024723, 9245985, 15880681, 12114496, 29743074, 31630786, 32503579, 34008892, 32300199, 33201366, 32573726, 8640225)

PP3, PM1, PM2_supporting, PS3, PS4

This sequence change replaces arginine, which is basic and polar, with glutamine, which is neutral and polar, at codon 411 of the ACVRL1 protein (p.Arg411Gln). This variant is present in population databases (rs121909284, gnomAD 0.007%). This missense change has been observed in individuals with hereditary hemorrhagic telangiectasia (HHT) (PMID: 8640225, 15024723, 20414677, 23805858). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 8243). 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 with a positive predictive value of 95%. Experimental studies have shown that this missense change affects ACVRL1 function (PMID: 14684682, 20501893). This variant disrupts the p.Arg411 amino acid residue in ACVRL1. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 15024723, 20501893). 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.

PM1, PM5, PP2, PP3, PP4, PP5

Based on the classification scheme VCGS_Germline_v1.1.1, this variant is classified as Pathogenic. Following criteria are met: 0102 - Loss-of-function is a known mechanism of disease for this gene. (N) 0107 - This gene is known to be associated with autosomal dominant disease. (N) 0200 - Variant is predicted to result in a missense amino acid change from an arginine to a glutamine (exon 8). (N) 0251 - Variant is heterozygous. (N) 0302 - Variant is present in gnomAD <0.001 for a dominant condition (2 heterozygotes, 0 homozygotes). (P) 0501 - Missense variant consistently predicted to be damaging by multiple in silico tools or highly conserved with a major amino acid change. (P) 0601 - Variant affects at least one well-established (essential) functional domain or motif. This variant at residue 411 was shown to be essential for the function of the kinase domain (PMID: 20501893). (P) 0701 - Comparable variants have very strong previous evidence for pathogenicity. Alternate changes at the same residue, to tryptophan and proline, have previously been reported in multiple patients with HHT (ClinVar, HGMD, LOVD, PMID: 15024723). (P) 0801 - Strong previous evidence of pathogenicity in unrelated individuals. The variant has previously been classified as pathogenic and reported in multiple patients with HHT (ClinVar, HGMD, LOVD, PMID: 8640225, PMID: 31400083). (P) 0901 - Strong evidence for segregation with disease. The variant has been reported to segregate with disease in HHT families (PMID: 8640225, PMID: 31400083). (P) 1002 - Moderate functional evidence supporting abnormal protein function. Functional studies in transfected cells demonstrated that the variant resulted in a reduced ability of ACVRL1 to bind its ligand BMP9 (PMID: 20501893). (P) 1102 - Strong phenotype match. (P) 1208 - Inheritance information for this variant is not currently available. (N) Legend: (P) - Pathogenic, (N) - Neutral, (B) - Benign

The p.R411Q pathogenic mutation (also known as c.1232G>A), located in coding exon 7 of the ACVRL1 gene, results from a G to A substitution at nucleotide position 1232. The arginine at codon 411 is replaced by glutamine, an amino acid with highly similar properties.This mutation has been detected in multiple individuals with a clinical diagnosis of hereditary hemorrhagic telangiectasia (HHT) (Gedge F et al. J Molec Diag. 2007;9(2):258-265; T&oslash;rring PM et al. PLoS ONE, 2014 Mar;9:e90272), including an individual with a history of pulmonary hypertension (Harrison RE et al. J. Med. Genet., 2003 Dec;40:865-71). This amino acid position is located in the intracellular kinase domain, and a functional study found that p.R411Q interferes with downstream signaling activity of the protein (Ricard N et al. Blood. 2010: 116(9):1604-12). This variant is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). Two additional disease causing alterations have been described at the same codon, p.R411P and p.R411W (Gedge F et al. J Molec Diag. 2007;9(2):258-265; Trembath RC et al. N. Engl. J. Med., 2001 Aug;345:325-34). Based on the supporting evidence, this alteration is interpreted as a disease-causing mutation.