ClinVar Miner

Submissions for variant NM_133433.4(NIPBL):c.6893G>A (p.Arg2298His) (rs587784024)

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Total submissions: 3
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Genetic Services Laboratory, University of Chicago RCV000146705 SCV000194021 pathogenic Cornelia de Lange syndrome 1 2013-02-08 criteria provided, single submitter clinical testing
GeneDx RCV000524005 SCV000617442 pathogenic not provided 2018-12-03 criteria provided, single submitter clinical testing The R2298H missense variant in the NIPBL gene has been reported as de novo and in association with Cornelia de Lange syndrome (Gillis et al., 2004; Bhuiyan et al., 2006). This variant is not observed in large population cohorts (Lek et al., 2016; 1000 Genomes Consortium et al., 2015; Exome Variant Server). R2298H is a conservative amino acid substitution, which is not likely to impact secondary protein structure as these residues share similar properties. However, this substitution occurs at a position that is conserved in mammals, and in silico analysis predicts this variant is probably damaging to the protein structure/function. Other missense variants in the same residue (R2298S/C/L) and nearby (S2296G) have been reported in the Human Gene Mutation Database in association with Cornelia de Lange syndrome (Stenson et al., 2014), supporting the functional importance of this region of the protein.
Invitae RCV000146705 SCV000775592 pathogenic Cornelia de Lange syndrome 1 2017-12-12 criteria provided, single submitter clinical testing This sequence change replaces arginine with histidine at codon 2298 of the NIPBL protein (p.Arg2298His). The arginine residue is moderately conserved and there is a small physicochemical difference between arginine and histidine. This variant is not present in population databases (ExAC no frequency). This variant has been reported to be de novo in individuals affected with Cornelia de Lange syndrome (PMID: 15318302). ClinVar contains an entry for this variant (Variation ID: 159211). Experimental studies have shown that this missense change results in precocious sister chromatid separation (PSCS) (PMID: 16100726) and in reduced expression of RNA-processing genes (PMID: 26725122). A different missense substitution at this codon (p.Arg2298Ser) has been determined to be pathogenic (PMID: 16236812). 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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