ClinVar Miner

Submissions for variant NM_000020.2(ACVRL1):c.1124A>G (p.Tyr375Cys) (rs1085307416)

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Total submissions: 2
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Invitae RCV000792743 SCV000932057 pathogenic Telangiectasia, hereditary hemorrhagic, type 2 2020-02-29 criteria provided, single submitter clinical testing This sequence change replaces tyrosine with cysteine at codon 375 of the ACVRL1 protein (p.Tyr375Cys). The tyrosine residue is highly conserved and there is a large physicochemical difference between tyrosine and cysteine. This variant is not present in population databases (ExAC no frequency). This variant has been observed to segregate with hereditary hemorrhagic telangiectasia (HHT) in a family (Invitae), and has been reported in an unrelated individual with HHT and pulmonary arterial hypertension (PMID: 23919827). ClinVar contains an entry for this variant (Variation ID: 426024). 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.Tyr375 amino acid residue in ACVRL1. Other variant(s) that disrupt this residue have been observed in individuals with ACVRL1-related conditions (PMID: 12843319), suggesting that it is a clinically significant residue. As a result, variants that disrupt this residue are likely to be causative of disease. For these reasons, this variant has been classified as Pathogenic.
Medical & Molecular Genetics Group,University of Lincoln RCV000488853 SCV000576332 pathogenic Pulmonary arterial hypertension related to hereditary hemorrhagic telangiectasia no assertion criteria provided literature only

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