ClinVar Miner

Submissions for variant NM_017617.5(NOTCH1):c.1093C>T (p.Arg365Cys)

dbSNP: rs1064795070
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Total submissions: 2
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000480413 SCV000570514 likely pathogenic not provided 2016-05-26 criteria provided, single submitter clinical testing The R365C variant in the NOTCH1 gene has not been reported previously as a germline pathogenic variant, nor as a benign variant, to our knowledge. The R365C variant was not observed in approximately 6500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, indicating it is not a common benign variant in these populations. The R365C 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. In addition, this substitution occurs at a position that is conserved across species. However, in silico analysis is inconsistent in its predictions as to whether or not the variant is damaging to the protein structure/function. The R365C variant is a strong candidate for a pathogenic variant, however the possibility it may be a rare benign variant cannot be excluded.
Invitae RCV002526596 SCV003459548 uncertain significance Adams-Oliver syndrome 5 2022-03-05 criteria provided, single submitter clinical testing This variant is not present in population databases (gnomAD no frequency). 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. Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is not expected to disrupt NOTCH1 protein function. ClinVar contains an entry for this variant (Variation ID: 421340). This variant has not been reported in the literature in individuals affected with NOTCH1-related conditions. This sequence change replaces arginine, which is basic and polar, with cysteine, which is neutral and slightly polar, at codon 365 of the NOTCH1 protein (p.Arg365Cys).

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