ClinVar Miner

Submissions for variant NM_133433.4(NIPBL):c.3109A>G (p.Lys1037Glu)

gnomAD frequency: 0.00001  dbSNP: rs587783916
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Total submissions: 4
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Genetic Services Laboratory, University of Chicago RCV000146565 SCV000193862 uncertain significance Cornelia de Lange syndrome 1 2013-02-08 criteria provided, single submitter clinical testing
GeneDx RCV000439281 SCV000513936 uncertain significance not provided 2016-03-21 criteria provided, single submitter clinical testing A variant of unknown significance has been identified in the NIPBL gene. The K1037E variant has not been published as a pathogenic variant, nor has it been reported as a benign polymorphism to our knowledge. It was not observed in approximately 6,500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, indicating it is not a common benign variant in these populations. The K1037E 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. This substitution occurs at a position that is highly conserved across species. In silico analysis predicts this variant is probably damaging to the protein structure/function. However, missense mutations in nearby residues have not been reported in the Human Gene Mutation Database in association with NIPBL-related disorders (Stenson et al., 2009). Therefore, based on the currently available information, it is unclear whether this variant is a pathogenic variant or a rare benign variant.
Invitae RCV000146565 SCV001232995 uncertain significance Cornelia de Lange syndrome 1 2023-01-30 criteria provided, single submitter clinical testing 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. Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) has been performed at Invitae for this missense variant, however the output from this modeling did not meet the statistical confidence thresholds required to predict the impact of this variant on NIPBL protein function. ClinVar contains an entry for this variant (Variation ID: 159072). This variant has not been reported in the literature in individuals affected with NIPBL-related conditions. The frequency data for this variant in the population databases is considered unreliable, as metrics indicate poor data quality at this position in the gnomAD database. This sequence change replaces lysine, which is basic and polar, with glutamic acid, which is acidic and polar, at codon 1037 of the NIPBL protein (p.Lys1037Glu).
Genome-Nilou Lab RCV000146565 SCV002055949 uncertain significance Cornelia de Lange syndrome 1 2021-07-15 criteria provided, single submitter clinical testing

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