ClinVar Miner

Submissions for variant NM_000118.3(ENG):c.1195del (p.Arg399fs) (rs1131691444)

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Total submissions: 4
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000494014 SCV000582141 pathogenic not provided 2017-05-11 criteria provided, single submitter clinical testing The c.1195delA pathogenic variant in the ENG gene has been reported previously in multiple individuals with HHT (Bayrak-Toydemir et al., 2006; Sadick et al., 2009; Nishida et al., 2012). Furthermore, the c.1195delA variant has not been observed in large population cohorts (Lek et al., 2016; 1000 Genomes Consortium et al., 2015; Exome Variant Server). The c.1195delA variant causes a shift in reading frame starting at codon arginine 399, changing it to a glycine, and creating a premature stop codon at position 22 of the new reading frame, denoted p.Arg399GlyfsX22. 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. Moreover, other frameshift variants in the ENG 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 RCV000999934 SCV000883790 pathogenic Hereditary hemorrhagic telangiectasia type 1 2018-09-18 criteria provided, single submitter clinical testing The ENG c.1195delA; p.Arg399fs variant is reported in the literature in multiple individuals with symptoms or a clinical diagnosis of HHT (Bayrak-Toydemir 2004, Bayrak-Toydemir 2006, Nishida 2012, Sadick 2009). Additionally, ARUP has documented segregation of this variant with disease in affected individuals of multiple families. This variant is reported in ClinVar (Variation ID: 429544), but it is absent from general population databases (Exome Variant Server, Genome Aggregation Database), indicating it is not a common polymorphism. This variant causes a frameshift by deleting a single nucleotide, 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: Bayrak-Toydemir P et al. Genotype-phenotype correlation in hereditary hemorrhagic telangiectasia: mutations and manifestations. Am J Med Genet A. 2006 Mar 1;140(5):463-70. 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. 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. Sadick H et al. Mutation analysis of Endoglin" and "Activin receptor-like kinase" genes in German patients with hereditary hemorrhagic telangiectasia and the value of rapid genotyping using an allele-specific PCR-technique. BMC Med Genet. 2009 Jun 9;10:53. doi: 10.1186/1471-2350-10-53. "
Invitae RCV001206848 SCV001378179 pathogenic Hereditary hemorrhagic telangiectasia 2020-07-30 criteria provided, single submitter clinical testing This sequence change creates a premature translational stop signal (p.Arg399Glyfs*22) in the ENG 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 variant has been observed in an individual affected with hereditary hemorrhagic telangiectasia (PMID: 22991266). ClinVar contains an entry for this variant (Variation ID: 429544). Loss-of-function variants in ENG are known to be pathogenic (PMID: 15879500, 20656886, 22385575). For these reasons, this variant has been classified as Pathogenic.
NIHR Bioresource Rare Diseases, University of Cambridge RCV000999934 SCV001439480 pathogenic Hereditary hemorrhagic telangiectasia type 1 2018-01-01 criteria provided, single submitter research PVS1+PM2+PP4

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