ClinVar Miner

Submissions for variant NM_000020.2(ACVRL1):c.1324G>A (p.Val442Met) (rs1085307421)

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Total submissions: 2
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Invitae RCV000814063 SCV000954459 uncertain significance Hereditary hemorrhagic telangiectasia type 2 2018-12-24 criteria provided, single submitter clinical testing This sequence change replaces valine with methionine at codon 442 of the ACVRL1 protein (p.Val442Met). The valine residue is highly conserved and there is a small physicochemical difference between valine and methionine. This variant is not present in population databases (ExAC no frequency). This variant has been observed in individuals affected with pulmonary arterial hypertetension and clinical features of hereditary hemorrhagic telangiectasia (PMID: 20056902, Invitae). ClinVar contains an entry for this variant (Variation ID: 426030). Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or 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 create or strengthen a splice site, but this prediction has not been confirmed by published transcriptional studies. This variant disrupts the p.Val442 amino acid residue in ACVRL1. Other variant(s) that disrupt this residue have been observed in individuals with ACVRL1-related conditions (PMID: 18498373), which suggests that this may be a clinically significant amino acid residue. 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.
Medical & Molecular Genetics Group,University of Lincoln RCV000488495 SCV000576338 pathogenic Pulmonary arterial hypertension related to hereditary hemorrhagic telangiectasia no assertion criteria provided literature only

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