ClinVar Miner

Submissions for variant NM_000020.2(ACVRL1):c.1249A>T (p.Ile417Phe) (rs141653630)

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Total submissions: 2
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
CSER _CC_NCGL, University of Washington RCV000735961 SCV000864150 likely benign Hereditary hemorrhagic telangiectasia 2015-07-01 criteria provided, single submitter research Found in patient having exome sequencing for an unrelated indication. Patient is a 56 year old female who reports no history of nosebleeds or telangiectasias. This interpretation considers GERP score and allele frequency data, in addition to published reports of the variant in the literature, available at the time of review.
Invitae RCV001245321 SCV001418602 uncertain significance Telangiectasia, hereditary hemorrhagic, type 2 2019-10-25 criteria provided, single submitter clinical testing This sequence change replaces isoleucine with phenylalanine at codon 417 of the ACVRL1 protein (p.Ile417Phe). The isoleucine residue is highly conserved and there is a small physicochemical difference between isoleucine and phenylalanine. This variant is present in population databases (rs141653630, ExAC 0.03%), and has an allele count higher than expected for a pathogenic variant (PMID: 28166811). This variant has been observed in an individual referred for testing for hereditary hemorrhagic telangiectasia (HHT) (PMID: 21158752), and also has been observed in combination with a pathogenic allele in ENG in an individual affected with HHT, which suggests that this c.1249A>T variant was not the primary cause of disease (PMID: 26176610). Experimental studies have shown that this missense change is not associated with a significant impact on protein expression or function (PMID: 26176610). 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.

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