ClinVar Miner

Submissions for variant NM_017617.5(NOTCH1):c.5776C>T (p.Arg1926Cys) (rs199652954)

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Total submissions: 3
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Ambry Genetics RCV000248613 SCV000320347 uncertain significance Cardiovascular phenotype 2015-11-06 criteria provided, single submitter clinical testing Lines of evidence used in support of classification: Rarity in general population databases (dbsnp, esp, 1000 genomes),In silico models in agreement (deleterious) and/or completely conserved position in appropriate species,Insufficient or conflicting evidence
GeneDx RCV000429642 SCV000535033 uncertain significance not provided 2018-03-06 criteria provided, single submitter clinical testing A variant of uncertain significance has been identified in the NOTCH1 gene. The R1926C variant has not been published as pathogenic or been reported as benign to our knowledge. The R1926C variant is observed in 19/273566 (0.007%) alleles from individuals of multiple ethnic backgrounds in large population cohorts (Lek et al., 2016). The R1926C 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. Finally, in-silico analyses, including protein predictors and evolutionary conservation, support a deleterious effect.
Invitae RCV000792055 SCV000931327 uncertain significance Adams-Oliver syndrome 5 2018-10-08 criteria provided, single submitter clinical testing This sequence change replaces arginine with cysteine at codon 1926 of the NOTCH1 protein (p.Arg1926Cys). The arginine residue is highly conserved and there is a large physicochemical difference between arginine and cysteine. This variant is present in population databases (rs199652954, ExAC 0.01%). This variant has not been reported in the literature in individuals with NOTCH1-related disease. ClinVar contains an entry for this variant (Variation ID: 264419). 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.

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