Submissions for variant NM_000020.3(ACVRL1):c.269G>A (p.Cys90Tyr)

dbSNP: rs863223410

Total submissions: 3

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000196221	SCV000249628	pathogenic	not provided	2015-03-11	criteria provided, single submitter	clinical testing	p.Cys90Tyr (C90Y) TGC>TAC: c.269 G>A in exon 3 of the ACVRL1 gene (NM_000020.2). The C90Y mutation in the ACVRL1 gene has been reported previously in association with HHT and was absent from at least 144 control individuals (Lesca et al., 2006; Gedge et al., 2007). Similarly, the C90Y mutation was not observed in approximately 6,400 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, indicating it is not a common benign variant in these populations. The C90Y variant is a non-conservative amino acid substitution, which is likely to impact secondary protein structure as these residues differ in polarity, charge, size and/or other properties. This substitution occurs at a position that is conserved across species. Furthermore, the C90 residue participates in disulfide bonding and is thought to be important to the protein structure/function (Scotti et al., 2011). Another mutation in the same residue (C90W), as well as mutations in nearby residues (C89Y, C95R, N96D) have been reported in association with HHT, further supporting the functional importance of this residue and of thisregion of the protein. In summary, C90Y in the ACVRL1 gene is interpreted as a disease-causing mutation. This variant was found in HHT-ARRHYTHMIA panel(s).
NIHR Bioresource Rare Diseases, University of Cambridge	RCV001262078	SCV001439463	likely pathogenic	Telangiectasia, hereditary hemorrhagic, type 2	2018-01-01	criteria provided, single submitter	research	PM2+PP2+PP4
Ambry Genetics	RCV002426928	SCV002742727	pathogenic	Cardiovascular phenotype	2020-08-14	criteria provided, single submitter	clinical testing	The p.C90Y pathogenic mutation (also known as c.269G>A), located in coding exon 2 of the ACVRL1 gene, results from a G to A substitution at nucleotide position 269. The cysteine at codon 90 is replaced by tyrosine, an amino acid with highly dissimilar properties. This mutation was identified in two individuals with a clinical diagnosis of hereditary hemorrhagic telangiectasia (Lesca G et al. Hum. Mutat., 2006 Jun;27:598; Gedge F et al. J Mol Diagn, 2007 Apr;9:258-65). Based on internal structural analysis, p.C90Y results in loss of a clinically relevant disulfide motif (Townson SA et al. J. Biol. Chem., 2012 Aug;287:27313-25). Two other alterations at the same codon, p.C90W (c.270C>G) and p.C90F (c.269G>T), have been described in individuals with suspected or confirmed HHT (Komiyama M et al. J. Hum. Genet., 2014 Jan;59:37-41; 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). This amino acid position is highly conserved in available vertebrate species. 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.