ClinVar Miner

Submissions for variant NM_133433.4(NIPBL):c.2479_2480del (p.Arg827fs) (rs398124465)

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Total submissions: 6
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Genetic Services Laboratory, University of Chicago RCV000146547 SCV000193843 pathogenic Cornelia de Lange syndrome 1 2013-02-08 criteria provided, single submitter clinical testing
EGL Genetic Diagnostics,Eurofins Clinical Diagnostics RCV000082485 SCV000225096 pathogenic not provided 2012-08-03 criteria provided, single submitter clinical testing
GeneDx RCV000082485 SCV000565326 pathogenic not provided 2017-03-13 criteria provided, single submitter clinical testing The c.2479_2480delAG pathogenic variant in the NIPBL gene has been reported previously in association with Cornelia de Lange Syndrome (Gillis et al., 2004; Bhuiyan et al., 2006; Pie et al., 2010). This variant is not observed in large population cohorts (Lek et al., 2016; Exome Variant Server). The deletion causes a frameshift starting with codon Arginine 827, changes this amino acid to a Glycine residue and creates a premature Stop codon at position 2 of the new reading frame, denoted p.Arg827GlyfsX2. This pathogenic variant is predicted to cause loss of normal protein function either through protein truncation or nonsense-mediated mRNA decay.
Baylor Genetics RCV000146547 SCV000747066 pathogenic Cornelia de Lange syndrome 1 2018-03-08 criteria provided, single submitter clinical testing
Invitae RCV000146547 SCV000934470 pathogenic Cornelia de Lange syndrome 1 2018-10-04 criteria provided, single submitter clinical testing This sequence change creates a premature translational stop signal (p.Arg827Glyfs*2) in the NIPBL gene. It is expected to result in an absent or disrupted protein product. This variant is not present in population databases (ExAC no frequency). This variant has been observed in several individuals affected with Cornelia de Lange syndrome (PMID: 15318302, 20358602, 17661813, 20824775). ClinVar contains an entry for this variant (Variation ID: 96336). Experimental studies have shown that this nonsense change results in chromatin decompaction in patient cells (PMID: 23760082) and contributes to dysregulation of many genes responsible for normal heart development (PMID: 29348408). Loss-of-function variants in NIPBL are known to be pathogenic (PMID: 15318302, 19763162, 23505322, 29995837). For these reasons, this variant has been classified as Pathogenic.
OMIM RCV000146547 SCV000022385 pathogenic Cornelia de Lange syndrome 1 2004-10-01 no assertion criteria provided literature only

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