ClinVar Miner

Submissions for variant NM_000501.4(ELN):c.800-2A>G (rs727503027)

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Total submissions: 2
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Invitae RCV000150636 SCV000553216 pathogenic Supravalvar aortic stenosis 2017-07-27 criteria provided, single submitter clinical testing This sequence change affects an acceptor splice site in intron 15 of the ELN gene. It is expected to disrupt RNA splicing and likely results in an absent or disrupted protein product. This variant is not present in population databases (ExAC no frequency). Loss-of-function variants in ELN are known to be pathogenic (PMID: 9215670, 11175284). This particular variant was reported in individuals with supravalvular aortic stenosis (PMID: 9215670, Invitae). This variant is also known as IVS15-2A>G in the literature. ClinVar contains an entry for this variant (Variation ID: 163387). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site, but this prediction has not been confirmed by published transcriptional studies. Donor and acceptor splice site variants typically lead to a loss of protein function (PMID: 16199547), and loss-of-function variants in ELN are known to be pathogenic (PMID: 11175284). For these reasons, this variant has been classified as Pathogenic.
Laboratory for Molecular Medicine,Partners HealthCare Personalized Medicine RCV000150636 SCV000197971 pathogenic Supravalvar aortic stenosis 2011-05-27 criteria provided, single submitter clinical testing The 800-2A>G variant has been reported in 2 individuals with SVAS and was absent from more than 750 control chromosomes (Li 1997). In addition, this variant was observed to segregate with disease in 4 affected family members. Furthermore, t his variant is predicted to cause abnormal splicing because the nucleotide subst itution occurs in the highly conserved splice consensus sequence. Splice-site al terations are a reported cause of SVAS in the ELN gene (Human Gene Mutation Data base, HGMD). In summary, this variant meets our pathogenicity criteria (http://p cpgm.partners.org/LMM).

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