ClinVar Miner

Submissions for variant NM_000020.3(ACVRL1):c.625+1G>T

dbSNP: rs1940767034
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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 RCV001211959 SCV001383527 pathogenic Telangiectasia, hereditary hemorrhagic, type 2 2019-10-10 criteria provided, single submitter clinical testing For these reasons, this variant has been classified as Pathogenic. Donor and acceptor splice site variants typically lead to a loss of protein function (PMID: 16199547), and loss-of-function variants in ACVRL1 are known to be pathogenic (PMID: 15879500). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site, but this prediction has not been confirmed by published transcriptional studies. Disruption of this splice site has been observed in several individuals affected with hereditary hemorrhagic telangiectasia (PMID: 27291782, Invitae). This variant is not present in population databases (ExAC no frequency). This sequence change affects a donor splice site in intron 5 of the ACVRL1 gene. It is expected to disrupt RNA splicing and likely results in an absent or disrupted protein product.
Ambry Genetics RCV002365953 SCV002656434 pathogenic Cardiovascular phenotype 2018-11-23 criteria provided, single submitter clinical testing The c.625+1G>T intronic pathogenic mutation results from a G to T substitution one nucleotide after coding exon 4 of the ACVRL1 gene. This nucleotide position is highly conserved in available vertebrate species. Using the BDGP and ESEfinder splice site prediction tools, this alteration is predicted to abolish the native splice donor site; 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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