ClinVar Miner

Submissions for variant NM_000020.2(ACVRL1):c.1126A>G (p.Met376Val) (rs1555153277)

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Total submissions: 1
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Invitae RCV000542069 SCV000639387 likely pathogenic Hereditary hemorrhagic telangiectasia type 2 2018-11-20 criteria provided, single submitter clinical testing This sequence change replaces methionine with valine at codon 376 of the ACVRL1 protein (p.Met376Val). The methionine residue is highly conserved and there is a small physicochemical difference between methionine and valine. This variant is not present in population databases (ExAC no frequency). This variant has been reported in the literature in several individuals affected with hereditary hemorrhagic telangiectasia (HHT) (PMID: 16690726, 17786384, 17384219, 16123970) as well as in one individual with suspected HHT (PMID: 15024723). Algorithms developed to predict the effect of missense changes on protein structure and function do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Probably Damaging"; Align-GVGD: "Class C15"). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may alter RNA splicing, but this prediction has not been confirmed by published transcriptional studies. In summary, this variant is a rare missense change that is absent from the general population and it has been reported in several affected individuals. This evidence indicates that the variant is pathogenic, but additional data is needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic.

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