ClinVar Miner

Submissions for variant NM_017617.5(NOTCH1):c.839A>G (p.Asn280Ser) (rs367825691)

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Total submissions: 2
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Fulgent Genetics,Fulgent Genetics RCV000764821 SCV000895972 uncertain significance Aortic valve disorder; Adams-Oliver syndrome 5 2018-10-31 criteria provided, single submitter clinical testing
Invitae RCV000471470 SCV000548962 uncertain significance Adams-Oliver syndrome 5 2018-12-26 criteria provided, single submitter clinical testing This sequence change replaces asparagine with serine at codon 280 of the NOTCH1 protein (p.Asn280Ser). The asparagine residue is highly conserved and there is a small physicochemical difference between asparagine and serine. The frequency data for this variant in the population databases is considered unreliable, as metrics indicate poor data quality at this position in the ExAC database. This variant has been reported in the literature in an individual affected with coarctation of the aorta (PMID: 26820064). ClinVar contains an entry for this variant (Variation ID: 409078). Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be disruptive, but these predictions have not been confirmed by published functional studies. Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may alter RNA splicing, but this prediction has not been confirmed by published transcriptional studies. In summary, this variant is a rare missense change with uncertain impact on protein function. It has been reported in both the population and affected individuals, but the available evidence is currently insufficient to determine its role in disease. Therefore, it has been classified as a Variant of Uncertain Significance.

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