ClinVar Miner

Submissions for variant NM_000020.2(ACVRL1):c.265T>G (p.Cys89Gly) (rs1555152520)

Minimum review status: Collection method:
Minimum conflict level:
ClinVar version:
Total submissions: 1
Download table as spreadsheet
Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Invitae RCV000640446 SCV000762037 uncertain significance Telangiectasia, hereditary hemorrhagic, type 2 2018-03-24 criteria provided, single submitter clinical testing This sequence change replaces cysteine with glycine at codon 89 of the ACVRL1 protein (p.Cys89Gly). The cysteine residue is highly conserved and there is a large physicochemical difference between cysteine and glycine. This variant is not present in population databases (ExAC no frequency). This variant has not been reported in the literature in individuals with ACVRL1-related disease. 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, but these predictions have not been confirmed by published functional studies and their clinical significance is uncertain. In summary, this variant is a novel missense change affecting a residue crucial for protein stability and function. Although cysteine substitutions located in ACVRL1 extravellular domain are likely deleterious, further genetic and/or functional data is needed to conclusively interpret this variant. Therefore, it has been classified as a Variant of Uncertain Significance.

The information on this website is not intended for direct diagnostic use or medical decision-making without review by a genetics professional. Individuals should not change their health behavior solely on the basis of information contained on this website. Neither the University of Utah nor the National Institutes of Health independently verfies the submitted information. If you have questions about the information contained on this website, please see a health care professional.