ClinVar Miner

Submissions for variant NM_000020.3(ACVRL1):c.525+1del

dbSNP: rs1060503249
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Total submissions: 2
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Labcorp Genetics (formerly Invitae), Labcorp RCV000476471 SCV000552417 pathogenic Telangiectasia, hereditary hemorrhagic, type 2 2024-05-08 criteria provided, single submitter clinical testing This sequence change affects a splice site in intron 4 of the ACVRL1 gene. It is expected to disrupt RNA splicing. Variants that disrupt the donor or acceptor splice site typically lead to a loss of protein function (PMID: 16199547), and loss-of-function variants in ACVRL1 are known to be pathogenic (PMID: 15879500). This variant is not present in population databases (gnomAD no frequency). Disruption of this splice site has been observed in individual(s) with epistaxis and telangiectasias (PMID: 21158752; Invitae). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 411315). For these reasons, this variant has been classified as Pathogenic.
Ambry Genetics RCV004022871 SCV005032347 pathogenic Cardiovascular phenotype 2020-08-14 criteria provided, single submitter clinical testing The c.525+1delG variant results from a deletion of 1 nucleotide at position c.525+1 and involves the canonical splice donor site after coding exon 3 of the ACVRL1 gene. This mutation was detected in an individual with epistaxis as well as cutaneous and gastrointestinal telangiectasias (McDonald J et al. Clin. Genet., 2011 Apr;79:335-44). The canonical splice donor site is highly conserved in available vertebrate species. Using the BDGP and ESEfinder splice site prediction tools, this alteration is predicted to create a new alternate splice donor site utilizing the last nucleotide of exon 3, which would result in a subsequent translational frameshift with a predicted alternate stop codon; however, direct evidence is unavailable. Alterations that disrupt the canonical splice site are expected to cause aberrant splicing, resulting in an abnormal protein or a transcript that is subject to nonsense-mediated mRNA decay. As such, this alteration is classified as a disease-causing mutation.

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