ClinVar Miner

Submissions for variant NM_000118.3(ENG):c.1309C>T (p.Arg437Trp) (rs1434169817)

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Total submissions: 2
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
ARUP Laboratories, Molecular Genetics and Genomics,ARUP Laboratories RCV000756074 SCV000883789 pathogenic Hereditary hemorrhagic telangiectasia type 1 2019-06-01 criteria provided, single submitter clinical testing The ENG c.1309C>T; p.Arg437Trp variant (rs1434169817) is reported in the literature in individuals with symptoms of HHT (Bossler 2006, Gedge 2007), and has been identified by our laboratory in several unrelated individuals affected with HHT. Additionally, a different alteration at this codon (p.Arg437Gln) has also been identified by our laboratory in multiple affected individuals and is considered pathogenic. The p.Arg437Trp variant is absent from general population databases (Exome Variant Server, Genome Aggregation Database), indicating it is not a common polymorphism. Based on available information, this variant is considered to be pathogenic. REFERENCES Bossler AD et al. Novel mutations in ENG and ACVRL1 identified in a series of 200 individuals undergoing clinical genetic testing for hereditary hemorrhagic telangiectasia (HHT): correlation of genotype with phenotype. Hum Mutat. 2006 Jul;27(7):667-75. Gedge F et al. Clinical and analytical sensitivities in hereditary hemorrhagic telangiectasia testing and a report of de novo mutations. J Mol Diagn. 2007 Apr;9(2):258-65.
Invitae RCV001062873 SCV001227696 pathogenic Hereditary hemorrhagic telangiectasia 2020-08-26 criteria provided, single submitter clinical testing This sequence change replaces arginine with tryptophan at codon 437 of the ENG protein (p.Arg437Trp). The arginine residue is moderately conserved and there is a moderate physicochemical difference between arginine and tryptophan. This variant is not present in population databases (ExAC no frequency). This variant has been observed in several individuals affected with hereditary hemorrhagic telangiectasia or isolated pulmonary ateriovenous malformations (PMID: 16752392, 21158752, 20414677, 23535011). ClinVar contains an entry for this variant (Variation ID: 618082). This variant has been reported not to substantially affect ENG protein function (PMID: 22022569). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may create or strengthen a splice site, but this prediction has not been confirmed by published transcriptional studies. This variant disrupts the p.Arg437 amino acid residue in ENG. Other variant(s) that disrupt this residue have been observed in individuals with ENG-related conditions (PMID: 21158752, 24001356), suggesting that it is a clinically significant residue. As a result, variants that disrupt this residue are likely to be causative of disease. For these reasons, this variant has been classified as Pathogenic.

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