ClinVar Miner

Submissions for variant NM_000020.3(ACVRL1):c.1217G>A (p.Trp406Ter)

dbSNP: rs1060503235
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Total submissions: 2
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
ClinGen Hereditary Hemorrhagic Telangiectasia Variant Curation Expert Panel, ClinGen RCV000475631 SCV004805885 pathogenic Telangiectasia, hereditary hemorrhagic, type 2 2024-03-15 reviewed by expert panel curation The NM_000020.3: c.1217G>A (p.Trp406Ter) variant in ACVRL1 is a nonsense variant predicted to cause a premature stop codon in biologically relevant exon 8 (out of 10) leading to nonsense mediated decay in a gene in which loss-of-function is an established disease mechanism (PVS1). This variant is absent from gnomAD v2.1.1 (PM2_Supporting). This variant has been reported in a proband with a phenotype consistent of HHT (PS4_Supporting; Internal lab contributors). In summary, this variant meets the criteria to be classified as pathogenic for autosomal dominant hereditary hemorrhagic telangiectasia based on the ACMG/AMP criteria applied, as specified by the ClinGen Hereditary Hemorrhagic Telangiectasia Variant Curation Expert Panel: PVS1, PM2_Supporting, PS4_Supporting (specification version 1.0.0; 1/4/2024).
Labcorp Genetics (formerly Invitae), Labcorp RCV000475631 SCV000552400 pathogenic Telangiectasia, hereditary hemorrhagic, type 2 2016-11-26 criteria provided, single submitter clinical testing For these reasons, this variant has been classified as Pathogenic. While this particular variant has not been reported in the literature, loss-of-function variants in ACVRL1 are known to be pathogenic (PMID: 15879500). This sequence change creates a premature translational stop signal at codon 406 (p.Trp406*) of the ACVRL1 gene. It is expected to result in an absent or disrupted protein product.

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