ClinVar Miner

Submissions for variant NM_000020.2(ACVRL1):c.924C>A (p.Cys308Ter) (rs1555153131)

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Total submissions: 3
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Invitae RCV000542741 SCV000639410 pathogenic Hereditary hemorrhagic telangiectasia type 2 2018-09-11 criteria provided, single submitter clinical testing This sequence change creates a premature translational stop signal (p.Cys308*) in the ACVRL1 gene. It is expected to result in an absent or disrupted protein product. This variant is not present in population databases (ExAC no frequency). This particular variant has been reported in the literature in individuals with hereditary hemorrhagic telangiectasia (HHT) (PMID: 9245985, 16123970). ClinVar contains an entry for this variant (Variation ID: 464771). Loss-of-function variants in ACVRL1 are known to be pathogenic (PMID: 15879500). For these reasons, this variant has been classified as Pathogenic.
GeneDx RCV000598771 SCV000709907 pathogenic not provided 2018-02-27 criteria provided, single submitter clinical testing The C308X pathogenic variant in the ACVRL1 gene has been reported previously in several unrelated individuals with a clinical diagnosis of HHT and was shown to segregate with disease in several affected members of one family (Berg et al., 1997; Argyriou et al., 2005; Lenato et al., 2006; Olivieri et al., 2007). Additionally, this variant is not observed in large population cohorts (Lek et al., 2016). The C308X variant is predicted to cause loss of normal protein function either by protein truncation or nonsense-mediated mRNA decay. Moreover, functional studies show that only wild type transcripts were detected in peripheral blood leukocytes from an individual harboring the C308X variant (Berg et al., 1997). Furthermore, other nonsense variants in the ACVRL1 gene have been reported in Human Gene Mutation Database in association with HHT (Stenson et al., 2014), indicating that loss of function is a mechanism of disease for this gene.
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories RCV000598771 SCV000884966 pathogenic not provided 2018-03-29 criteria provided, single submitter clinical testing The ACVRL1 c.924C>A; p.Cys308Ter variant is reported in the literature in individuals with HHT (Bayrak-Toydemir 2004, Berg 1997, Lenato 2006, Olivieri 2007), and classified as pathogenic in ClinVar (Variation ID: 464771). This variant is absent from the general population databases (1000 Genomes Project, Exome Variant Server, Genome Aggregation Database), indicating it is not a common polymorphism. This variant induces an early termination codon and predicted to result in a truncated protein or mRNA subject to nonsense-medicated decay. Based on available information, this variant is considered pathogenic. REFERENCES Bayrak-Toydemir P et al. Hereditary hemorrhagic telangiectasia: an overview of diagnosis and management in the molecular era for clinicians. Genet Med. 2004 Jul-Aug;6(4):175-91. Berg JN et al. The activin receptor-like kinase 1 gene: genomic structure and mutations in hereditary hemorrhagic telangiectasia type 2. Am J Hum Genet. 1997 Jul;61(1):60-7. Lenato GM et al. DHPLC-based mutation analysis of ENG and ALK-1 genes in HHT Italian population. Hum Mutat. 2006 Feb;27(2):213-4. Olivieri C et al. Analysis of ENG and ACVRL1 genes in 137 HHT Italian families identifies 76 different mutations (24 novel). Comparison with other European studies. J Hum Genet. 2007;52(10):820-9.

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