ClinVar Miner

Submissions for variant NM_000020.2(ACVRL1):c.905T>C (p.Leu302Pro) (rs1565594217)

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Total submissions: 3
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
ARUP Laboratories, Molecular Genetics and Genomics,ARUP Laboratories RCV000755785 SCV000883357 uncertain significance not provided 2017-06-27 criteria provided, single submitter clinical testing The ACVRL1 c.905T>C; p.Leu302Pro variant has not been reported in the literature or gene-specific databases. However, a different variant at this codon, p.Leu302Arg, has been reported to segregate with disease in a German family with hereditary hemorrhagic telangiectasia (Schulte 2005). The highly conserved leucine at codon 302 is located in the protein kinase domain, and computational algorithms (SIFT, PolyPhen2, MutationTaster) predict the p.Leu302Pro variant to be damaging to the protein. Due to the limited information regarding p.Leu302Pro, its clinical significance is uncertain at this time. REFERENCES Schulte C et al. High frequency of ENG and ALK1/ACVRL1 mutations in German HHT patients. Hum Mutat. 2005 Jun;25(6):595.
Invitae RCV001040697 SCV001204286 uncertain significance Telangiectasia, hereditary hemorrhagic, type 2 2019-10-07 criteria provided, single submitter clinical testing This sequence change replaces leucine with proline at codon 302 of the ACVRL1 protein (p.Leu302Pro). The leucine residue is highly conserved and there is a moderate physicochemical difference between leucine and proline. This variant is not present in population databases (ExAC no frequency). This variant has been observed in an individual affected with clinical features of hereditary hemorrhagic telangiectasia (Invitae). 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.Leu302 amino acid residue in ACVRL1. Other variant(s) that disrupt this residue have been observed in individuals with ACVRL1-related conditions (PMID: 15880681), 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.
NIHR Bioresource Rare Diseases, University of Cambridge RCV001040697 SCV001439472 likely pathogenic Telangiectasia, hereditary hemorrhagic, type 2 2018-01-01 criteria provided, single submitter research PM2+PM1+PP4

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