ClinVar Miner

Submissions for variant NM_000118.3(ENG):c.721_725del (p.Ser241fs) (rs1064794219)

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Total submissions: 3
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000486392 SCV000568243 pathogenic not provided 2017-03-22 criteria provided, single submitter clinical testing The c.721_725delAGCTG pathogenic variant in the ENG gene has been previously reported as a notnovel mutation" associated with clinical features of epistaxis, telangiectasia, and cerebral AVM in acohort of patients referred for HHT genetic testing (McDonald et al., 2011). This variant causes ashift in reading frame starting at codon serine 241, changing it to an arginine, and creating apremature stop codon at position 91 of the new reading frame, denoted p.Ser241ArgfsX91. Thispathogenic variant is expected to result in either an abnormal, truncated protein product or loss ofprotein from this allele through nonsense-mediated mRNA decay. Multiple other downstreamframeshift 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.721_725delAGCTG variant has not been observed in largepopulation cohorts (Lek et al., 2016; 1000 Genomes Consortium et al., 2015; Exome Variant Server)."
Invitae RCV000693436 SCV000821305 pathogenic Hereditary hemorrhagic telangiectasia 2019-06-29 criteria provided, single submitter clinical testing This sequence change creates a premature translational stop signal (p.Ser241Argfs*91) 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 reported in individuals affected with hereditary hemorraghic telangiectasia (PMID: 21158752, 20414677). ClinVar contains an entry for this variant (Variation ID: 419981). 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.
ARUP Laboratories, Molecular Genetics and Genomics,ARUP Laboratories RCV001287654 SCV001474364 pathogenic Hereditary hemorrhagic telangiectasia type 1 2019-07-23 criteria provided, single submitter clinical testing The ENG c.721_725delAGCTG; p.Ser241fs variant (rs1064794219) is reported in individuals with HHT (McDonald 2011, Richards-Yutz 2010), and is classified as pathogenic in ClinVar (Variation ID: 419981). This variant 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 five 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 McDonald J et al. Molecular diagnosis in hereditary hemorrhagic telangiectasia: findings in a series tested simultaneously by sequencing and deletion/duplication analysis. Clin Genet. 2011 Apr;79(4):335-44. Richards-Yutz J et al. Update on molecular diagnosis of hereditary hemorrhagic telangiectasia. Hum Genet. 2010 Jul;128(1):61-77.

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