ClinVar Miner

Submissions for variant NM_000020.3(ACVRL1):c.1246+2T>C

dbSNP: rs1555153382
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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 RCV000525999 SCV000639389 pathogenic Telangiectasia, hereditary hemorrhagic, type 2 2023-07-19 criteria provided, single submitter clinical testing For these reasons, this variant has been classified as Pathogenic. This sequence change affects a donor splice site in intron 8 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 hereditary hemorrhagic telangiectasia (PMID: 16429404, 16752392, 20414677). ClinVar contains an entry for this variant (Variation ID: 464755). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site.
Ambry Genetics RCV002395380 SCV002674069 pathogenic Cardiovascular phenotype 2023-07-14 criteria provided, single submitter clinical testing The c.1246+2T>C intronic pathogenic mutation results from a T to C substitution two nucleotides after coding exon 7 in the ACVRL1 gene. This alteration, also designated as c.1376+2T>G has been report in subjects with hereditary hemorrhagic telangiectasia (HHT) (Lenato GM et al. Hum. Mutat., 2006 Feb;27:213-4; Richards-Yutz J et al. Hum. Genet., 2010 Jul;128:61-77; Karlsson T et al. Ups. J. Med. Sci., 2018 Sep;123:153-157). This variant is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). This nucleotide position is highly conserved in available vertebrate species. In silico splice site analysis predicts that this alteration will weaken the native splice donor site and will result in the creation or strengthening of a novel splice donor site. 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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