ClinVar Miner

Submissions for variant NM_000020.3(ACVRL1):c.1438C>T (p.Leu480Phe)

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Total submissions: 2
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Ambry Genetics RCV002394303 SCV002702873 uncertain significance Cardiovascular phenotype 2015-04-29 criteria provided, single submitter clinical testing The p.L480F variant (also known as c.1438C>T), located in coding exon 9 of the ACVRL1 gene, results from a C to T substitution at nucleotide position 1438. The leucine at codon 480 is replaced by phenylalanine, an amino acid with highly similar properties. This variant was observed in one patient meeting diagnostic Curacao criteria for HHT (Olivieri C 2007, J. Hum. Genet; 52(10):820-9). This variant was not reported in population based cohorts in the following databases: Database of Single Nucleotide Polymorphisms (dbSNP), NHLBI Exome Sequencing Project (ESP), and 1000 Genomes Project. In the ESP, this variant was not observed in 6503 samples (13006 alleles) with coverage at this position. In addition, this alteration is predicted to be deleterious by in silico analysis. Since clinical data on this variant is still limited at this time, its clinical significance is unclear.
Labcorp Genetics (formerly Invitae), Labcorp RCV003509750 SCV004294166 pathogenic Telangiectasia, hereditary hemorrhagic, type 2 2023-06-24 criteria provided, single submitter clinical testing ClinVar contains an entry for this variant (Variation ID: 1772647). This missense change has been observed in individual(s) with hereditary hemorrhagic telangiectasia (PMID: 17786384, 32300199). This variant is not present in population databases (gnomAD no frequency). This sequence change replaces leucine, which is neutral and non-polar, with phenylalanine, which is neutral and non-polar, at codon 480 of the ACVRL1 protein (p.Leu480Phe). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is expected to disrupt ACVRL1 protein function. For these reasons, this variant has been classified as Pathogenic.

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