ClinVar Genomic variation as it relates to human health

The de novo c.6440T>G (p.Val2147Gly) variant identified in the NIPBL gene substitutes a very well conserved Valine for Glycine at amino acid 2147/2805 (exon 37/47). This variant has not previously been reported in public variant repositories (ClinVar and LOVD), and is absent from population databases (gnomAD v2.1.1 and v3.1.2, TOPMed Freeze 8), suggesting it is not a common benign variant in the populations represented in those databases. In silico algorithms predict this variant to be Pathogenic (REVEL; score: 0.822) and Damaging (SIFT; score:0.00) to the canonical transcript. The p.Val2147Gly variant has been reported in an individual with a clinical diagnosis of Cornelia de Lange syndrome, however detailed clinical information for this individual was not provided [Patient 38, Supp Table S1; PMID:30614194]. The p.Val2147 residue is within the HEAT domain region of NIPBL where pathogenic missense variants are often reported [PMID:25125236, 24038889]. Given its presence de novo here, absence in population databases, in silico prediction of a damaging effect on protein function, and observation in an individual in the literature with clinical diagnosis of Cornelia de Lange, the de novo c.6440T>G (p.Val2147Gly) variant identified in the NIPBL gene isreported as Likely Pathogenic.