ClinVar Miner

Submissions for variant NM_000020.2(ACVRL1):c.200G>A (p.Arg67Gln) (rs863223414)

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Total submissions: 3
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories RCV000200439 SCV000883351 pathogenic not provided 2017-07-18 criteria provided, single submitter clinical testing The ACVRL1 c.200G>A; p.Arg67Gln variant (rs863223414) has been reported in multiple unrelated individuals and families with hereditary hemorrhagic telangiectasia (Berg 1997, Canzonieri 2014, Giordano 2006, Lenato 2006, Olivieri 2007, Schulte 2005). This variant is reported in the ClinVar database (Variation ID: 212803), and is absent from general population databases (1000 Genomes Project, Exome Variant Server, Genome Aggregation Database). The arginine at codon 67 is highly conserved, and computational algorithms (SIFT, MutationTaster, Align GVGD) predict this variant to be damaging to the protein. Taken together, this variant is considered pathogenic. REFERENCES Link to ClinVar database for p.Arg67Gln: https://www.ncbi.nlm.nih.gov/clinvar/variation/212803/ 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. Canzonieri C et al. Endoscopic evaluation of gastrointestinal tract in patients with hereditary hemorrhagic telangiectasia and correlation with their genotypes. Genet Med. 2014 Jan;16(1):3-10. Giordano P et al. Screening for children from families with Rendu-Osler-Weber disease: from geneticist to clinician. J Thromb Haemost. 2006 Jun;4(6):1237-45. 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. Schulte C et al. High frequency of ENG and ALK1/ACVRL1 mutations in German HHT patients. Hum Mutat. 2005 Jun;25(6):595.
GeneDx RCV000200439 SCV000249633 pathogenic not provided 2018-02-02 criteria provided, single submitter clinical testing The R67Q pathogenic variant in the ACVRL1 gene has been reported in numerous individuals with HHT (Berg et. al., 1997; Schulte et al., 2005; Sadick et al., 2009; Lenato et al., 2006; Canzonieri et al., 2014). Berg et al. (1997) originally described R67Q in an individual with HHT and was absent from at least 200 control chromosomes. R67Q has been observed in at least three other individuals with HHT (Schulte et al. 2005; Sadick et al., 2009; Canzonieri et al., 2014). Family studies demonstrated R67Q co-segregated with HHT in two families and was absent from 200 control alleles (Lenato et al., 2006). R67Q results in a semi-conservative amino acid substitution of Arginine at a position that is conserved across species. Variants in this same residue (R67W) and in nearby residues (H66P, G68C, C69R, C69Y, C69F) have been reported in association with HHT, further supporting the functional importance of this region of the protein. Furthermore, the R67Q mutation 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. In summary, R67Q in the ACVRL1 gene is interpreted as a pathogenic variant. This variant was found in HHT-PANCARD panel(s).
Invitae RCV000534448 SCV000639398 pathogenic Hereditary hemorrhagic telangiectasia type 2 2018-11-07 criteria provided, single submitter clinical testing This sequence change replaces arginine with glutamine at codon 67 of the ACVRL1 protein (p.Arg67Gln). The arginine residue is highly conserved and there is a small physicochemical difference between arginine and glutamine. This variant is not present in population databases (ExAC no frequency). This variant has been reported in several individuals affected with hemorrhagic telangiectasia (PMID: 9245985, 23722869, 15880681, 18498373, 17786384, 16706966). ClinVar contains an entry for this variant (Variation ID: 212803). Experimental studies have shown that this missense change has a deleterious effect on protein function (PMID: 10187774, 14684682). A different missense substitution at this codon (p.Arg67Trp) has been determined to be pathogenic (PMID: 22377182, 22553411, 17786384, 18285823). This suggests that the arginine residue is critical for ACVRL1 protein function and that other missense substitutions at this position may also be pathogenic. For these reasons, this variant has been classified as Pathogenic.

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