ClinVar Miner

Submissions for variant NM_000020.3(ACVRL1):c.1246+5G>A

dbSNP: rs1940838881
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Total submissions: 3
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
NIHR Bioresource Rare Diseases, University of Cambridge RCV001262027 SCV001439400 likely pathogenic Telangiectasia, hereditary hemorrhagic, type 2 2018-01-01 criteria provided, single submitter research PM2+PP3+PP4
Ambry Genetics RCV002393671 SCV002674070 uncertain significance Cardiovascular phenotype 2022-03-16 criteria provided, single submitter clinical testing The c.1246+5G>A intronic variant results from a G to A substitution 5 nucleotides after coding exon 7 in the ACVRL1 gene. This variant was reported in a hereditary hemorrhagic telangiectasia (HHT) cohort with limited details provided (Shovlin CL et al. Blood, 2020 10;136:1907-1918). 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 result in the creation or strengthening of a novel splice donor site. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear.
Invitae RCV001262027 SCV004504745 uncertain significance Telangiectasia, hereditary hemorrhagic, type 2 2023-02-21 criteria provided, single submitter clinical testing ClinVar contains an entry for this variant (Variation ID: 982448). This sequence change falls in intron 8 of the ACVRL1 gene. It does not directly change the encoded amino acid sequence of the ACVRL1 protein. It affects a nucleotide within the consensus splice site. This variant is not present in population databases (gnomAD no frequency). This variant has been observed in individual(s) with hereditary hemorrhagic telangiectasia (PMID: 32573726). Variants that disrupt the consensus splice site are a relatively common cause of aberrant splicing (PMID: 17576681, 9536098). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may create or strengthen a splice site. 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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