ClinVar Miner

Submissions for variant NM_000020.2(ACVRL1):c.145dup (p.Ala49fs) (rs863223415)

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Total submissions: 2
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000195435 SCV000249636 pathogenic not provided 2016-11-23 criteria provided, single submitter clinical testing The c.145dupG pathogenic variant in the ACVRL1 gene, also denoted as 140insG, c.144_145insG and c.145_146insG, has been previously reported in multiple individuals in association with HHT (Klaus et al., 1998; Olivieri et al, 2002; Olivieri et al., 2007; Fontalba et al., 2008; Lux et al, 2013). This variant causes a shift in reading frame starting at codon Alanine 49, changing it to a Glycine, and creating a premature stop codon at position 120 of the new reading frame, denoted p.Ala49GlyfsX120. This pathogenic variant is expected to result in either an abnormal, truncated protein product or loss of protein from this allele through nonsense-mediated mRNA decay. Multiple other frameshift variants in the ACVRL1 gene have been reported in HGMD in association with HHT (Stenson et al., 2014). Furthermore, the c.145dupG variant was not observed in approximately 6,500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, indicating it is not a common benign variant in these populations.
Invitae RCV000459586 SCV000552418 pathogenic Hereditary hemorrhagic telangiectasia type 2 2018-12-26 criteria provided, single submitter clinical testing This sequence change inserts 1 nucleotide in exon 3 of the ACVRL1 mRNA (c.145dupG), causing a frameshift at codon 49. This creates a premature translational stop signal (p.Ala49Glyfs*120) and is expected to result in an absent or disrupted protein product. This variant is not present in population databases (ExAC no frequency). Truncating variants in ACVRL1 are known to be pathogenic. This particular truncation has been reported in the literature in individuals affected with hereditary hemorrhagic telangiectasia (HHT) (PMID: 10694922, 12114496). This variant is also known in the literature as c.140insG. ClinVar contains an entry for this variant (Variation ID: 212805). For these reasons, this variant has been classified as Pathogenic.

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