ClinVar Miner

Submissions for variant NM_017617.5(NOTCH1):c.7397C>T (p.Thr2466Met) (rs369167555)

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Total submissions: 2
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Invitae RCV000229341 SCV000290311 uncertain significance Adams-Oliver syndrome 5 2018-02-08 criteria provided, single submitter clinical testing This sequence change replaces threonine with methionine at codon 2466 of the NOTCH1 protein (p.Thr2466Met). The threonine residue is moderately conserved and there is a moderate physicochemical difference between threonine and methionine. This variant is present in population databases (rs369167555, ExAC 0.007%). This variant has been reported in the literature in an individual affected with hypoplastic left heart syndrome (PMID: 26820064). ClinVar contains an entry for this variant (Variation ID: 241169). Algorithms developed to predict the effect of missense changes on protein structure and function do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Possibly Damaging"; Align-GVGD: "Class C0"). 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 RCV000493754 SCV000582292 uncertain significance not provided 2017-11-17 criteria provided, single submitter clinical testing A variant of uncertain significance has been identified in the NOTCH1 gene. The T2466M variant has not been published as pathogenic or been reported as benign to our knowledge. The T2466M variant is not observed at a significant frequency in large population cohorts (Lek et al., 2016; 1000 Genomes Consortium et al., 2015; Exome Variant Server). Additionally, T2466M is reported as a variant of uncertain significance by one other laboratory in ClinVar (SCV000290311.2, Landrum et al., 2016). This substitution occurs at a position that is not conserved across species, and in silico analysis predicts this variant likely does not alter the protein structure/function. Furthermore, no missense variants in nearby residues have been reported in the Human Gene Mutation Database (Stenson et al., 2014). Nevertheless, the T2466M variant is a non-conservative amino acid substitution, which is likely to impact secondary protein structure as these residues differ in polarity, charge, size and/or other properties.

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