ClinVar Miner

Submissions for variant NM_017617.5(NOTCH1):c.4066C>T (p.Arg1356Cys) (rs587778567)

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Total submissions: 3
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000658393 SCV000780165 uncertain significance not provided 2018-05-31 criteria provided, single submitter clinical testing A variant of uncertain significance has been identified in the NOTCH1 gene. The R1356C variant has been published in one European individual from a cohort of individuals with no known personal or family history indicative of a cancer predisposition syndrome who underwent whole genome sequencing (Bodian et al., 2014), although additional clinical details unrelated to cancer history were not described. The R1356C variant is also not observed in large population cohorts (Lek et al., 2016). The R1356C 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-silico analyses, including protein predictors and evolutionary conservation, support a deleterious effect. However, this variant has not been observed in a significant number of affected individuals, and it lacks both segregation and functional studies which would further clarify its pathogenicity.
Invitae RCV001201674 SCV001372756 uncertain significance Adams-Oliver syndrome 5 2019-10-29 criteria provided, single submitter clinical testing This sequence change replaces arginine with cysteine at codon 1356 of the NOTCH1 protein (p.Arg1356Cys). The arginine residue is moderately conserved and there is a large physicochemical difference between arginine and cysteine. This variant is present in population databases (rs587778567, ExAC 0.01%). This variant has not been reported in the literature in individuals with NOTCH1-related conditions. ClinVar contains an entry for this variant (Variation ID: 134933). 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 disruptive, 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.
ITMI RCV000121683 SCV000085881 not provided not specified 2013-09-19 no assertion provided reference population

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