ClinVar Miner

Submissions for variant NM_000020.3(ACVRL1):c.231C>G (p.Cys77Trp)

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Total submissions: 1
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Invitae RCV001224004 SCV001396177 pathogenic Telangiectasia, hereditary hemorrhagic, type 2 2019-08-08 criteria provided, single submitter clinical testing This sequence change replaces cysteine with tryptophan at codon 77 of the ACVRL1 protein (p.Cys77Trp). The cysteine residue is highly conserved and there is a large physicochemical difference between cysteine and tryptophan. This variant is not present in population databases (ExAC no frequency). This variant has been observed in several individuals with clinical features of hereditary hemorrhagic telangiectasia (HHT) (PMID: 10694922, 16690726, Invitae). This variant has been reported to affect ACVRL1 protein function (PMID: 20501893, 14684682). This variant disrupts the p.Cys77 amino acid residue in ACVRL1. Other variant(s) that disrupt this residue have been observed in individuals with ACVRL1-related conditions (PMID: 26176610, 17786384), which suggests that this may be a clinically significant amino acid residue. 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). For these reasons, this variant has been classified as Pathogenic.

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