ClinVar Miner

Submissions for variant NM_001077401.2(ACVRL1):c.1030T>C (p.Cys344Arg) (rs1592224412)

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Total submissions: 2
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Invitae RCV000812604 SCV000952922 pathogenic Telangiectasia, hereditary hemorrhagic, type 2 2018-10-02 criteria provided, single submitter clinical testing This sequence change replaces cysteine with arginine at codon 344 of the ACVRL1 protein (p.Cys344Arg). The cysteine residue is highly conserved and there is a large physicochemical difference between cysteine and arginine. This variant is not present in population databases (ExAC no frequency). This variant has been reported in several individuals with hereditary hemorrhagic telangiectasia (HHT) and observed to segregate with HHT in a family (PMID: 16470787, 18673552, 16752392, 19767588). 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. Variants that disrupt the p.Cys344 amino acid residue in ACVRL1 have been observed in affected individuals (PMID: 10767348, 14684682, 15880681, 16540754, 16542389, 17384219, 12114496). This suggests that it is a clinically significant residue, and that other variants that disrupt this residue are likely to be causative of disease. For these reasons, this variant has been classified as Pathogenic.
NIHR Bioresource Rare Diseases, University of Cambridge RCV001003754 SCV001162197 pathogenic Pulmonary arterial hypertension no assertion criteria provided research

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