ClinVar Miner

Submissions for variant NM_000020.3(ACVRL1):c.982C>T (p.His328Tyr)

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Total submissions: 1
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Invitae RCV001052514 SCV001216726 likely pathogenic Telangiectasia, hereditary hemorrhagic, type 2 2019-12-15 criteria provided, single submitter clinical testing This sequence change replaces histidine with tyrosine at codon 328 of the ACVRL1 protein (p.His328Tyr). The histidine residue is highly conserved and there is a moderate physicochemical difference between histidine and tyrosine. This variant is not present in population databases (ExAC no frequency). This variant has been observed in individuals affected with clinical features of hereditary hemorrhagic telangiectasia (PMID: 24196379, 17384219, 25970827, 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. This variant disrupts the p.His328 amino acid residue in ACVRL1. Other variant(s) that disrupt this residue have been observed in individuals with ACVRL1-related conditions (PMID: 20414677, 29650961, 16470589), which suggests that this may be a clinically significant amino acid residue. 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.

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