ClinVar Genomic variation as it relates to human health

Based on the classification scheme VCGS_Germline_v1.3.4, this variant is classified as Pathogenic. Following criteria are met: 0103 - Dominant negative and loss of function are known mechanisms of disease in this gene and are associated with hereditary hemorrhagic telangiectasia type 2 (MIM#600376). Protein truncating variants are known to cause disease through a loss of function mechanism, while missense variants have been associated with both loss of function and dominant negative mechanisms (PMIDs: 26176610, 16470589, 16282348). (I) 0107 - This gene is associated with autosomal dominant disease. (I) 0115 - Variants in this gene are known to have variable expressivity. Clinical expression is known to be extremely variable and age-dependent (PMID: 19767588). (I) 0200 - Variant is predicted to result in a missense amino acid change from arginine to glutamine. (I) 0251 - This variant is heterozygous. (I) 0302 - Variant is present in gnomAD (v3) <0.001 for a dominant condition (2 heterozygotes, 0 homozygotes). (SP) 0309 - An alternative amino acid change at the same position has been observed in gnomAD (v3) (1 heterozygote, 0 homozygotes). (I) 0502 - Missense variant with conflicting in silico predictions and uninformative conservation. (I) 0600 - Variant is located in the annotated kinase domain (PMID: 20501893). (I) 0701 - Other missense variants comparable to the one identified in this case have very strong previous evidence for pathogenicity. p.(Arg374Trp) has been reported in multiple families with hereditary hemorrhagic telangiectasia (HHT) and it is believed to have resulted from a founder effect (ClinVar; PMID: 33919892). In addition, p.(Arg374Gly) has been reported in an individual with HHT (ClinVar). (SP) 0801 - This variant has strong previous evidence of pathogenicity in unrelated individuals with hereditary hemorrhagic telangiectasia and it is also believed to have resulted from a founder effect (ClinVar; PMID: 33919892). (SP) 1002 - This variant has moderate functional evidence supporting abnormal protein function. Mutagenesis studies demonstrated that both p.(Arg374Gln) and p.(Arg374Trp) did not bind to the specific ligand BMP9 (PMID: 20501893). (SP) 1208 -Inheritance information for this variant is not currently available in this individual. (I) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign

The ACVRL1 c.1121G>A; p.Arg374Gln variant (rs1060503248) has been reported in the literature in individuals with hereditary hemorrhagic telangiectasia (HHT) or pulmonary arterial hypertension (PAH) (Abdalla 2003, Harrison 2003, McDonald 2011, Yang 2018), and has been shown to have defective BMP9 ligand signaling (Ricard 2010). This variant has been reported in ClinVar (Variation ID: 411314) and is absent from the general population databases (Exome Variant Server, Genome Aggregation Database), indicating it is not a common polymorphism. The arginine at codon 374 is highly conserved, but computational analyses are uncertain whether this variant is neutral or deleterious (REVEL: 0.654). Another amino acid substitution at this codon (p.Arg374Trp) has been reported in multiple individuals with HHT and is considered disease-causing (Harrison 2003, Nishida 2012). Based on available information, the p.Arg374Gln variant is considered to be pathogenic. REFERENCES Abdalla SA et al. Disease-associated mutations in conserved residues of ALK-1 kinase domain. Eur J Hum Genet. 2003 Apr;11(4):279-87. Harrison RE et al. Molecular and functional analysis identifies ALK-1 as the predominant cause of pulmonary hypertension related to hereditary haemorrhagic telangiectasia. J Med Genet. 2003 Dec;40(12):865-71. 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. Nishida T et al. Brain arteriovenous malformations associated with hereditary hemorrhagic telangiectasia: gene-phenotype correlations. Am J Med Genet A. 2012 ; 158A(11): 2829-2834. Ricard N et al. Functional analysis of the BMP9 response of ALK1 mutants from HHT2 patients: a diagnostic tool for novel ACVRL1 mutations. Blood. 2010 Sep 2;116(9):1604-12. Yang H et al. Genetic analyses in a cohort of 191 pulmonary arterial hypertension patients. Respir Res. 2018 May 9;19(1):87.

This sequence change replaces arginine, which is basic and polar, with glutamine, which is neutral and polar, at codon 374 of the ACVRL1 protein (p.Arg374Gln). The frequency data for this variant in the population databases is considered unreliable, as metrics indicate poor data quality at this position in the gnomAD database. This missense change has been observed in individuals with hereditary hemorrhagic telangiectasia (PMID: 12700602, 18285823, 21158752, 25970827). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 411314). 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. Experimental studies have shown that this missense change affects ACVRL1 function (PMID: 20501893). This variant disrupts the p.Arg374 amino acid residue in ACVRL1. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 12700602, 15517393, 17384219, 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.

This sequence change is predicted to replace arginine with glutamine at codon 374 of the ACVRL1 protein (p.(Arg374Gln)). The arginine residue is evolutionarily conserved (100 vertebrates, UCSC), and is located in the protein kinase domain. There is a small physicochemical difference between arginine and glutamine. The variant is present in a single individual in a large population cohort (1/251,110 alleles in gnomAD v2.1). It is a recurrent variant that has been identified in multiple individuals with a clinical diagnosis of hereditary haemorrhagic telangiectasia (HHT), and segregates with disease in multiple families (PMID: 12700602, 12843319, 15517393, 17384219, 18673552, 18285823, 23919827, 25970827, 31511490). The variant alters the BMP9 response and reduces kinase activity in functional studies (PMID: 14684682, 20501893, 27869117). Multiple lines of computational evidence predict a deleterious effect for the missense substitution (5/6 algorithms). Two missense changes involving the same residue (p.Arg374Gly, p.Arg374Trp), but a larger physicochemical change, have been reported as pathogenic in HHT individuals (ClinVar). Based on the classification scheme RMH Modified ACMG Guidelines v1.4.0, this variant is classified as PATHOGENIC. Following criteria are met: PS4, PP1_Strong, PS3_Supporting, PM2_Supporting, PP3.

The p.R374Q pathogenic mutation (also known as c.1121G>A), located in coding exon 7 of the ACVRL1 gene, results from a G to A substitution at nucleotide position 1121. The arginine at codon 374 is replaced by glutamine, an amino acid with highly similar properties. This mutation was initially reported in in two possibly related hereditary hemorrhagic telangiectasia (HHT) families and was observed to segregate with disease in both families (Abdalla SA et al. Eur J Hum Genet, 2003 Apr;11:279-87). This mutation has been reported in additional individuals and families with HHT (Fontalba A et al. BMC Med. Genet., 2008 Aug;9:75; Chen YJ et al. Eur J Clin Invest, 2013 Oct;43:1016-24; McDonald J et al. Genet Med, 2020 07;22:1201-1205). The p.R374Q mutation is located in the intracellular kinase domain of the ALK1 protein, and in vitro functional studies showed this mutation had no functional activity in response to BMP9, a ligand for ALK1 (Ricard N et al. Blood, 2010 Sep;116:1604-12). Based on the supporting evidence, this alteration is interpreted as a disease-causing mutation.

Published functional studies in transfected cultured cells suggest that although ACVRL1 receptors harboring R374Q can bind BMP9 ligand at the cell surface, the BMP9 signaling response is impaired (PMID: 20501893); Segregates with HHT in at least two affected relatives from two families (PMID: 12700602, 23919827); 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: 18673552, 17384219, 23919827, 18285823, 14684682, 15517393, 17786384, 25970827, 21158752, 29743074, 26387786, 31511490, 34872578, 12700602, 32300199, 33919892, 20501893)

ACVRL1: PS4, PM1, PM5, PP1, PS3:Supporting

PP1_strong, PM2, PM5, PS3, PS4