ClinVar Miner

Submissions for variant NM_000020.3(ACVRL1):c.988G>C (p.Asp330His)

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Total submissions: 1
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Molecular Genetics, Royal Melbourne Hospital RCV003994713 SCV004812712 likely pathogenic Hereditary hemorrhagic telangiectasia 2023-03-30 criteria provided, single submitter clinical testing This sequence change in ACVRL1 is predicted to replace aspartic acid with histidine at codon 330, p.(Asp330His). The aspartic acid residue is highly conserved (99/99 vertebrates, UCSC), and is located at a critical residue for kinase activity in the HRD triad motif of the protein kinase domain (PMID: 16051269, 17095602). There is a moderate physicochemical difference between aspartic acid and histidine. This variant is absent from the population database gnomAD v2.1 and v3.1. This variant has been reported in at least two probands with a clinical diagnosis of hereditary haemhorragic telangiectasia (HHT, PMID: 24001356; Royal Melbourne Hospital). Multiple lines of computational evidence predict a deleterious effect for the missense substitution (6/6 algorithms). Other missense variants substituting the Asp330 residue have been reported in individuals with HHT, further demonstrating the importance of the amino acid in protein function (PMID: 12114496, 15517393, 17786384). Based on the classification scheme RMH Modified ACMG Guidelines v1.5.1, this variant is classified as LIKELY PATHOGENIC. Following criteria are met: PM1, PS4_Moderate, PM2_Supporting, PP3.

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