ClinVar Miner

Submissions for variant NM_000020.3(ACVRL1):c.206G>T (p.Cys69Phe)

dbSNP: rs1318118188
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Total submissions: 3
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Labcorp Genetics (formerly Invitae), Labcorp RCV000640447 SCV000762038 pathogenic Telangiectasia, hereditary hemorrhagic, type 2 2023-02-05 criteria provided, single submitter clinical testing This sequence change replaces cysteine, which is neutral and slightly polar, with phenylalanine, which is neutral and non-polar, at codon 69 of the ACVRL1 protein (p.Cys69Phe). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individuals with ACVRL1-related disease (PMID: 21158752; Invitae). ClinVar contains an entry for this variant (Variation ID: 533353). 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. This variant affects a cysteine residue located within the ACVRL1 protein ectodomain. Cysteine residues in this domain of ACVRL1 are involved in the formation of disulfide bridges critical for protein structure and stability (PMID: 22028876, 22718755, 22799562). In addition, missense substitutions within the ACVRL1 ectodomain affecting cysteine residues are overrepresented in patients with HHT (PMID: 20501893, 26176610 and www.hhtmutation.org). This variant disrupts the p.Cys69 amino acid residue in ACVRL1. Other variant(s) that disrupt this residue have been observed in individuals with ACVRL1-related conditions (PMID: 16525724), which suggests that this may be a clinically significant amino acid residue. For these reasons, this variant has been classified as Pathogenic.
Genetic Services Laboratory, University of Chicago RCV001816595 SCV002072113 pathogenic not provided 2017-08-02 criteria provided, single submitter clinical testing
Fulgent Genetics, Fulgent Genetics RCV000640447 SCV002793342 likely pathogenic Telangiectasia, hereditary hemorrhagic, type 2 2021-07-07 criteria provided, single submitter clinical testing

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