ClinVar Miner

Submissions for variant NM_017617.5(NOTCH1):c.1711G>A (p.Asp571Asn) (rs373125283)

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Total submissions: 2
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000494050 SCV000583364 uncertain significance not provided 2017-05-23 criteria provided, single submitter clinical testing A variant of uncertain significance has been identified in the NOTCH1 gene. The D571N variant has not been published as pathogenic or been reported as benign to our knowledge. Additionally, this variant is not observed in large population cohorts (Lek et al., 2016; 1000 Genomes Consortium et al., 2015; Exome Variant Server). The D571N variant is a semi-conservative amino acid substitution, which may impact secondary protein structure as these residues differ in some properties. However, this substitution occurs at a position not conserved across species and asparagine (N) is the wild-type residue at this position in at least one non-mammalian species. Finally, in silico analysis predicts this variant likely does not alter the protein structure/function.
Invitae RCV000541112 SCV000659379 uncertain significance Adams-Oliver syndrome 5 2018-10-31 criteria provided, single submitter clinical testing This sequence change replaces aspartic acid with asparagine at codon 571 of the NOTCH1 protein (p.Asp571Asn). The aspartic acid residue is moderately conserved and there is a small physicochemical difference between aspartic acid and asparagine. 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. ClinVar contains an entry for this variant (Variation ID: 430538). 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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