ClinVar Miner

Submissions for variant NM_000020.2(ACVRL1):c.406_409del (p.Gly136fs) (rs863223416)

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Total submissions: 3
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000196965 SCV000249637 pathogenic not provided 2016-12-07 criteria provided, single submitter clinical testing The c.406_409delGGTG pathogenic variant in the ACVRL1 gene has been reported in association with HHT in one affected proband out of a cohort of 50 patients, and was absent from >100 healthy individuals (Klaus et al.,1998). Furthermore, the c.406_409delGGTG 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. This variant causes a shift in reading frame starting at codon Glycine 136, changing it to a Serine, and creating a premature stop codon at position 28 of the new reading frame, denoted p.Gly136SerfsX28. 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. Other frameshift variants in the ACVRL1 gene have been reported in the Human Gene Mutation Database in association with HHT (Stenson et al., 2014).
Invitae RCV000694342 SCV000822782 pathogenic Telangiectasia, hereditary hemorrhagic, type 2 2019-06-20 criteria provided, single submitter clinical testing This sequence change creates a premature translational stop signal (p.Gly136Serfs*28) in the ACVRL1 gene. It is expected to result in an absent or disrupted protein product. This variant is present in population databases (rs750662466, ExAC 0.02%). This variant has been reported in an individual affected with hereditary hemorrhagic telangiectasia (HHT) (PMID: 10694922, 15879500). This variant is also described as p.G136fs in the literature. ClinVar contains an entry for this variant (Variation ID: 212806). Loss-of-function variants in ACVRL1 are known to be pathogenic (PMID: 15879500). For these reasons, this variant has been classified as Pathogenic.
ARUP Laboratories, Molecular Genetics and Genomics,ARUP Laboratories RCV000694342 SCV001473733 pathogenic Telangiectasia, hereditary hemorrhagic, type 2 2020-01-17 criteria provided, single submitter clinical testing The ACVRL1 c.406_409delGGTG; p.Gly136fs variant (rs863223416) is reported in the literature in an individual with HHT (Klaus 1998), and is reported in the ClinVar database (Variation ID: 212806). This variant is only observed on two alleles in the Genome Aggregation Database, indicating it is not a common polymorphism. This variant causes a frameshift by deleting four nucleotides, so it is predicted to result in a truncated protein or mRNA subject to nonsense-mediated decay. Based on available information, this variant is considered to be pathogenic. REFERENCES Klaus DJ et al. Novel missense and frameshift mutations in the activin receptor-like kinase-1 gene in hereditary hemorrhagic telangiectasia. Mutations in brief no. 164. Online. Hum Mutat. 1998;12(2):137.

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