ClinVar Miner

Submissions for variant NM_017617.5(NOTCH1):c.5560C>T (p.Arg1854Cys) (rs376689092)

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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 RCV000617738 SCV000739491 uncertain significance Cardiovascular phenotype 2017-07-19 criteria provided, single submitter clinical testing Lines of evidence used in support of classification: Insufficient evidence
Invitae RCV000814127 SCV000954527 uncertain significance Adams-Oliver syndrome 5 2018-08-30 criteria provided, single submitter clinical testing This sequence change replaces arginine with cysteine at codon 1854 of the NOTCH1 protein (p.Arg1854Cys). The arginine residue is highly conserved and there is a large physicochemical difference between arginine and cysteine. This variant is present in population databases (rs376689092, 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: 520079). 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.
Laboratory for Molecular Medicine,Partners HealthCare Personalized Medicine RCV000825407 SCV000966704 uncertain significance not specified 2018-10-24 criteria provided, single submitter clinical testing The p.Arg1854Cys variant in NOTCH1 has not been reported in the literature in in dividuals with aortic valve disease or Adams-Oliver syndrome, but has been repor ted as a variant of uncertain signficance in ClinVar (Variation ID# 520079). It has also been identified in 0.01% (3/23838) of African chromosomes by gnomAD (ht tp://gnomad.broadinstitute.org). Computational prediction tools and conservation analysis suggest that the variant may impact the protein, though this informati on is not predictive enough to determine pathogenicity. In summary, the clinical significance of the p.Arg1854Cys variant is uncertain. ACMG/AMP Criteria applie d: PM2_Supporting, PP3.

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