ClinVar Miner

Submissions for variant NM_000118.3(ENG):c.1195_1196del (p.Arg399fs) (rs1131691422)

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Total submissions: 3
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000494067 SCV000582092 likely pathogenic not provided 2017-05-02 criteria provided, single submitter clinical testing Although the c.1195_1196delAG likely pathogenic variant in the ENG gene has not been reported toour knowledge, this variant causes a shift in reading frame starting at codon arginine 399, changing itto a glycine, and creating a premature stop codon at position 2 of the new reading frame, denotedp.Arg399GlyfsX2. This likely pathogenic variant is expected to result in either an abnormal, truncatedprotein product or loss of protein from this allele through nonsense-mediated mRNA decay. Multipleother frameshift variants in the ENG gene have been reported in Human Gene Mutation Database inassociation with HHT (Stenson et al., 2014), indicating that loss of function is a mechanism of diseasefor this gene. Furthermore, the c.1195_1196delAG variant has not been observed in large populationcohorts (Lek et al., 2016; 1000 Genomes Consortium et al., 2015; Exome Variant Server).
ARUP Laboratories, Molecular Genetics and Genomics,ARUP Laboratories RCV001002195 SCV001160068 pathogenic Hereditary hemorrhagic telangiectasia type 1 2018-11-09 criteria provided, single submitter clinical testing The ENG c.1195_1196delAG; p.Arg399fs variant, to our knowledge, is not reported in the medical literature but is reported in ClinVar (Variation ID: 429506). Our laboratory has previously detected this variant in another individual affected with HHT. Additionally, a similar deletion (c.1195delA; p.Arg399fs) is associated with HHT and considered to be pathogenic (see link). The c.1195_1196delAG variant is absent from general population databases (1000 Genomes Project, Exome Variant Server, and Genome Aggregation Database), indicating it is not a common polymorphism. This variant causes a frameshift by deleting two nucleotides, 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 HHT ENG database link:
Invitae RCV001385796 SCV001585759 pathogenic Hereditary hemorrhagic telangiectasia 2020-09-11 criteria provided, single submitter clinical testing This sequence change creates a premature translational stop signal (p.Arg399Glyfs*2) 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 not been reported in the literature in individuals with ENG-related conditions. ClinVar contains an entry for this variant (Variation ID: 429506). Loss-of-function variants in ENG are known to be pathogenic (PMID: 15879500). For these reasons, this variant has been classified as Pathogenic.

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