ClinVar Miner

Submissions for variant NM_000020.2(ACVRL1):c.1135G>A (p.Glu379Lys) (rs1131691686)

Minimum review status: Collection method:
Minimum conflict level:
ClinVar version:
Total submissions: 3
Download table as spreadsheet
Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
ARUP Laboratories, Molecular Genetics and Genomics,ARUP Laboratories RCV000494459 SCV000883354 pathogenic not provided 2017-07-11 criteria provided, single submitter clinical testing The ACVRL1 c.1135G>A; p.Glu379Lys variant has been reported in several unrelated individuals diagnosed with hereditary hemorrhagic telangiectasia (Brakensiek 2008, Fontalba 2008, Kuehl 2005, Lenato 2006, Lesca 2004, Nishida 2012), and shown by functional assays to have a decreased BMP9 response and inability to properly localize to the cell surface (Alaa El Din 2015). This variant is reported in the ClinVar database (Variation ID: 429940), and observed in general population databases at a very low frequency of 0.0008 percent (2/246050 alleles, Genome Aggregation Database). The glutamate at codon 379 is a highly conserved residue in the protein kinase domain, and computational algorithms (SIFT, PolyPhen2, MutationTaster, Align GVGD) predict this variant to be damaging to the protein. Based on the above information, this variant is considered pathogenic. REFERENCES Link to ClinVar database for p.Glu379Lys: https://www.ncbi.nlm.nih.gov/clinvar/variation/429940/ Alaa El Din F et al. Functional and splicing defect analysis of 23 ACVRL1 mutations in a cohort of patients affected by Hereditary Hemorrhagic Telangiectasia. PLoS One. 2015 Jul 15;10(7):e0132111. Brakensiek K et al. Detection of a significant association between mutations in the ACVRL1 gene and hepatic involvement in German patients with hereditary haemorrhagic telangiectasia. Clin Genet. 2008 Aug;74(2):171-7. Fontalba A et al. Mutation study of Spanish patients with hereditary hemorrhagic telangiectasia. BMC Med Genet. 2008 Aug 1;9:75. Kuehl HK et al. Hepatic manifestation is associated with ALK1 in hereditary hemorrhagic telangiectasia: identification of five novel ALK1 and one novel ENG mutations. Hum Mutat. 2005 Mar;25(3):320. 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. Lesca G et al. Molecular screening of ALK1/ACVRL1 and ENG genes in hereditary hemorrhagic telangiectasia in France. Hum Mutat. 2004 Apr;23(4):289-99. Nishida T et al. Brain arteriovenous malformations associated with hereditary hemorrhagic telangiectasia: gene-phenotype correlations. Am J Med Genet A. 2012 Nov;158A(11):2829-34.
GeneDx RCV000494459 SCV000582632 likely pathogenic not provided 2016-04-20 criteria provided, single submitter clinical testing The E379K variant has been reported in multiple unrelated individuals from various ethnic backgrounds who have been diagnosed with HHT (Lesca et al., 2004; Brusgaard et al., 2004; Kuehl et al., 2005; Lenato et al., 2006; Brakensiek et al., 2008; Fontalba et al., 2008; Nishida et al., 2012). Considering all publications, the E379K variant was not observed in 576 control alleles (Lesca et al., 2004; Lenato et al., 2006). In addition, the E379K 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. The E379K variant is a non-conservative amino acid substitution, which is likely to impact secondary protein structure as these residues differ in polarity, charge, size and/or other properties. This substitution occurs at a position that is conserved across species. Furthermore, functional studies using the BMP9 response assay and Western blot analysis confirm that E379K has a negative impact on ACVRL1 receptor activity and protein maturation (El Din et al., 2015). A missense variant in the same residue (E379D) has been reported in the Human Gene Mutation Database in association with HHT (Stenson et al., 2014); however, the pathogenicity of this variant has not been definitively determined. Finally, despite the fact that several publications describe an association between the E379K variant in the ACVRL1 gene and HHT, family history information and segregation data was not provided.
Invitae RCV000554533 SCV000639388 pathogenic Hereditary hemorrhagic telangiectasia type 2 2017-02-03 criteria provided, single submitter clinical testing This sequence change replaces glutamic acid with lysine at codon 379 of the ACVRL1 protein (p.Glu379Lys). The glutamic acid residue is highly conserved and there is a small physicochemical difference between glutamic acid and lysine. This variant is not present in population databases (ExAC no frequency). This variant has been reported in many unrelated individuals affected with hereditary hemorrhagic telangiectasia (PMID: 15024723, 15712270, 16429404, 18498373, 22991266, 24603890). Experimental studies have shown that this missense change causes mis-localization of the protein (PMID: 26176610). For these reasons, this variant has been classified as Pathogenic.

The information on this website is not intended for direct diagnostic use or medical decision-making without review by a genetics professional. Individuals should not change their health behavior solely on the basis of information contained on this website. Neither the University of Utah nor the National Institutes of Health independently verfies the submitted information. If you have questions about the information contained on this website, please see a health care professional.