ClinVar Miner

Submissions for variant NM_017617.5(NOTCH1):c.17_18delinsTT (p.Ala6Val) (rs878855023)

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Total submissions: 3
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Invitae RCV000230821 SCV000290243 uncertain significance Adams-Oliver syndrome 5 2019-12-29 criteria provided, single submitter clinical testing This sequence change deletes 2 and inserts 2 nucleotides in exon 1 of the NOTCH1 mRNA (c.17_18delinsTT), replacing alanine with valine at codon 6 of the NOTCH1 protein (p.Ala6Val). The alanine residue is weakly conserved and there is a small physicochemical difference between alanine and valine. This variant is not present in population databases (ExAC no frequency) and has not been reported in the literature in individuals with a NOTCH1-related disease. ClinVar contains an entry for this variant (Variation ID: 241120). 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 tolerated, but these predictions have not been confirmed by published functional studies. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance.
GeneDx RCV000523117 SCV000621053 likely benign not specified 2017-11-21 criteria provided, single submitter clinical testing This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease.
CHEO Genetics Diagnostic Laboratory,Children's Hospital of Eastern Ontario RCV000769619 SCV000901016 uncertain significance Familial thoracic aortic aneurysm and aortic dissection 2016-09-08 criteria provided, single submitter clinical testing

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