ClinVar Miner

Submissions for variant NM_133433.4(NIPBL):c.5981A>G (p.Asn1994Ser)

gnomAD frequency: 0.00011  dbSNP: rs368028754
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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 RCV000146660 SCV000193972 benign not specified 2013-02-08 criteria provided, single submitter clinical testing
Illumina Laboratory Services, Illumina RCV001157612 SCV001319201 uncertain significance Cornelia de Lange syndrome 1 2018-01-12 criteria provided, single submitter clinical testing This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score, this variant could not be ruled out of causing disease and therefore its association with disease required further investigation. A literature search was performed for the gene, cDNA change, and amino acid change (if applicable). No publications were found based on this search. This variant was therefore classified as a variant of unknown significance for this disease.
Genome-Nilou Lab RCV001157612 SCV002054197 likely benign Cornelia de Lange syndrome 1 2021-07-15 criteria provided, single submitter clinical testing
Invitae RCV001157612 SCV004343737 uncertain significance Cornelia de Lange syndrome 1 2023-02-18 criteria provided, single submitter clinical testing This sequence change replaces asparagine, which is neutral and polar, with serine, which is neutral and polar, at codon 1994 of the NIPBL protein (p.Asn1994Ser). This variant is present in population databases (rs368028754, gnomAD 0.02%). This missense change has been observed in individual(s) with clinical features of NIPBL-related conditions (PMID: 15318302). ClinVar contains an entry for this variant (Variation ID: 159166). 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. 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.

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