Submissions for variant NM_000020.3(ACVRL1):c.830C>G (p.Thr277Arg)

Total submissions: 2

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
NIHR Bioresource Rare Diseases, University of Cambridge	RCV001262082	SCV001439469	likely pathogenic	Telangiectasia, hereditary hemorrhagic, type 2	2018-01-01	criteria provided, single submitter	research	PM2+PM1+PP4
Invitae	RCV001262082	SCV001545882	uncertain significance	Telangiectasia, hereditary hemorrhagic, type 2	2020-07-10	criteria provided, single submitter	clinical testing	This sequence change replaces threonine with arginine at codon 277 of the ACVRL1 protein (p.Thr277Arg). The threonine residue is highly conserved and there is a moderate physicochemical difference between threonine and arginine. This variant is not present in population databases (ExAC no frequency). This variant has been observed in individual(s) with clinical features of hereditary hemorrhagic telangiectasia (Invitae). 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. Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may create or strengthen a splice site, but this prediction has not been confirmed by published transcriptional studies. This variant disrupts the p.Thr277 amino acid residue in ACVRL1. Other variant(s) that disrupt this residue have been determined to be pathogenic ( PMID: 25970827, 20414677, Invitae). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance.