ClinVar Miner

Submissions for variant NM_000020.3(ACVRL1):c.649T>G (p.Trp217Gly)

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Total submissions: 2
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Ambry Genetics RCV002364125 SCV002658229 likely pathogenic Cardiovascular phenotype 2024-06-25 criteria provided, single submitter clinical testing The p.W217G variant (also known as c.649T>G), located in coding exon 5 of the ACVRL1 gene, results from a T to G substitution at nucleotide position 649. The tryptophan at codon 217 is replaced by glycine, an amino acid with highly dissimilar properties. This variant has been observed in at least one individual with a personal and/or family history that is consistent with hereditary hemorrhagic telangiectasia (HHT) (Ambry internal data; Richards-Yutz J et al. Hum Genet, 2010 Jul;128:61-77). This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. This variant is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). Based on the majority of available evidence to date, this variant is likely to be pathogenic.
Labcorp Genetics (formerly Invitae), Labcorp RCV005096951 SCV005836043 pathogenic Telangiectasia, hereditary hemorrhagic, type 2 2024-03-16 criteria provided, single submitter clinical testing This sequence change replaces tryptophan, which is neutral and slightly polar, with glycine, which is neutral and non-polar, at codon 217 of the ACVRL1 protein (p.Trp217Gly). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with clinical features of hereditary hemorrhagic telangiectasia (PMID: 20414677; Invitae). ClinVar contains an entry for this variant (Variation ID: 1753890). 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 with a positive predictive value of 95%. For these reasons, this variant has been classified as Pathogenic.

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