ClinVar Miner

Submissions for variant NM_017617.5(NOTCH1):c.1205C>T (p.Ser402Leu) (rs1037236860)

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Total submissions: 2
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000523401 SCV000620615 uncertain significance not provided 2017-09-06 criteria provided, single submitter clinical testing A variant of uncertain significance has been identified in the NOTCH1 gene. The S402L variant has not been published as pathogenic or been reported as benign to our knowledge. This variant is also not observed in large population cohorts (Lek et al., 2016; 1000 Genomes Consortium et al., 2015; Exome Variant Server). The S402L 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. However, while this substitution occurs at a position that is conserved in mammals, leucine (L) is the wild-type residue at this position in at least one non-mammalian species. Finally, in silico analysis is inconsistent in its predictions as to whether or not the variant is damaging to the protein structure/function.
Invitae RCV000700981 SCV000829761 uncertain significance Adams-Oliver syndrome 5 2018-01-31 criteria provided, single submitter clinical testing This sequence change replaces serine with leucine at codon 402 of the NOTCH1 protein (p.Ser402Leu). The serine residue is moderately conserved and there is a large physicochemical difference between serine and leucine. This variant is not present in population databases (ExAC no frequency). This variant has not been reported in the literature in individuals with NOTCH1-related disease. 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 and their clinical significance is uncertain. 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.

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