ClinVar Miner

Submissions for variant NM_133433.4(NIPBL):c.6892C>T (p.Arg2298Cys) (rs80358376)

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Total submissions: 2
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Genetic Services Laboratory, University of Chicago RCV000146704 SCV000194020 pathogenic Cornelia de Lange syndrome 1 2013-08-27 criteria provided, single submitter clinical testing
Invitae RCV000146704 SCV000827404 pathogenic Cornelia de Lange syndrome 1 2018-01-23 criteria provided, single submitter clinical testing This sequence change replaces arginine with cysteine at codon 2298 of the NIPBL protein (p.Arg2298Cys). The arginine residue is moderately conserved and there is a large physicochemical difference between arginine and cysteine. This variant is not present in population databases (ExAC no frequency). This variant has been reported in individuals affected with Cornelia de Lange syndrome (PMID: 15318302) and has been reported to arise de novo in at least 2 affected individuals (PMID: 23254390, 17661813). ClinVar contains an entry for this variant (Variation ID: 159210). Algorithms developed to predict the effect of missense changes on protein structure and function do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Probably Damaging"; Align-GVGD: "Class C0"). A different missense substitution at this codon (p.Arg2298His) has been determined to be pathogenic (PMID: 15318302, 16100726, 26725122). This suggests that the arginine residue is critical for NIPBL protein function and that other missense substitutions at this position may also be pathogenic. For these reasons, this variant has been classified as Pathogenic.

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