ClinVar Genomic variation as it relates to human health

This variant is not present in population databases (gnomAD no frequency). In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic. This variant disrupts the p.Cys90 amino acid residue in ACVRL1. Other variant(s) that disrupt this residue have been observed in individuals with ACVRL1-related conditions (PMID: 16705692; Invitae), which suggests that this may be a clinically significant amino acid residue. This variant affects a cysteine residue located within the ACVRL1 protein ectodomain. Cysteine residues in this domain of ACVRL1 are involved in the formation of disulfide bridges critical for protein structure and stability (PMID: 22028876, 22718755, 22799562). In addition, missense substitutions within the ACVRL1 ectodomain affecting cysteine residues are overrepresented in patients with HHT (PMID: 20501893, 26176610 and www.hhtmutation.org). 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 hereditary hemorrhagic telangiectasia (PMID: 24196379; Invitae). This sequence change replaces cysteine, which is neutral and slightly polar, with tryptophan, which is neutral and slightly polar, at codon 90 of the ACVRL1 protein (p.Cys90Trp).

The p.C90W pathogenic mutation (also known as c.270C>G), located in coding exon 2 of the ACVRL1 gene, results from a C to G substitution at nucleotide position 270. The cysteine at codon 90 is replaced by tryptophan, an amino acid with highly dissimilar properties. This alteration has been reported in an individual with epistaxis, telangiectases, hepatic arteriovenous malformation (AVM), and family history of suspected hereditary hemorrhagic telangiectasia (HHT) (Komiyama M et al. J. Hum. Genet., 2014 Jan;59:37-41; personal communication). Based on internal structural analysis, C90W disrupts a structurally important disulfide bond at a position with internal pathogenic variants (Townson SA et al. J. Biol. Chem., 2012 Aug;287:27313-25). Two other alterations at the same codon, p.C90Y (c.269G>A) and p.C90F (c.269G>T), have been described in individuals with suspected or confirmed HHT (Lesca G et al. Hum. Mutat., 2006 Jun;27:598; Gedge F et al. J Mol Diagn, 2007 Apr;9:258-65; Goulielmos GN et al. IJNTR, 2016 Feb;2(1):32-6). This variant was not reported in population-based cohorts in the Genome Aggregation Database (gnomAD). In addition, this alteration is predicted to be deleterious by in silico analysis. Based on the supporting evidence, this alteration is interpreted as a disease-causing mutation.