Total submissions: 2
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| Molecular Genetics, |
RCV002225163 | SCV002503662 | likely benign | Cornelia de Lange syndrome 1 | 2021-11-11 | criteria provided, single submitter | clinical testing | This sequence change is predicted to replace asparagine with serine at codon 393 of the NIPBL protein (p.(Asn393Ser)). The asparagine residue is moderately conserved (100 vertebrates, UCSC), and is not located in a known functional domain. There is a small physicochemical difference between asparagine and serine. The variant is present in a single individual in a large population cohort (1/143,238 alleles in gnomAD v3.0 and absent in gnomAD v2.1), and has not been reported in the relevant medical literature. The variant was found to be paternally inherited in an isolated case with syndromic intellectual disability (Royal Melbourne Hospital, Shariant) and identified in two individuals without syndromic features in the TOPMed cohort (https://bravo.sph.umich.edu). Multiple lines of computational evidence have conflicting predictions for the missense substitution (3/6 algorithms predict deleterious). Based on the classification scheme RMH ACMG Guidelines v1.4.0, this variant is classified as LIKELY BENIGN. Following criteria are met: BS2. |
| Victorian Clinical Genetics Services, |
RCV002225163 | SCV002767265 | likely benign | Cornelia de Lange syndrome 1 | 2021-05-06 | criteria provided, single submitter | clinical testing | Based on the classification scheme VCGS_Germline_v1.3.4, this variant is classified as Likely benign. Following criteria are met: 0102 - Loss of function is a known mechanism of disease in this gene and is associated with Cornelia de Lange syndrome 1 (CdL; MIM#122470). (I) 0107 - This gene is associated with autosomal dominant disease. (I) 0115 - Variants in this gene are known to have variable expressivity. Variants in the NIPBL gene have been associated with the classic and more severe form of CdL, however protein truncating variants in this gene seem to result in a more severe phenotype than missense and in-frame variants (PMID: 20301283). (I) 0200 - Variant is predicted to result in a missense amino acid change from asparagine to serine. (I) 0251 - This variant is heterozygous. (I) 0302 - Variant is present in gnomAD (v3) <0.001 for a dominant condition (1 heterozygote, 0 homozygotes). (SP) 0309 - An alternative amino acid change at the same position has been observed in gnomAD (v3) 1 heterozygote, 0 homozygotes). (I) 0502 - Missense variant with conflicting in silico predictions and uninformative conservation. (I) 0604 - Variant is not located in an established domain, motif, hotspot or informative constraint region. (I) 0710 - Another missense variant comparable to the one identified in this case has inconclusive previous evidence for pathogenicity. It has been reported in two individuals with atrioventricular septal defect who also harboured variants in other genes (CHD7 and CEP152), as well as in a control sample (PMID: 25996639). (I) 0807 - This variant has no previous evidence of pathogenicity. (I) 0905 - No published segregation evidence has been identified for this variant. (I) 1007 - No published functional evidence has been identified for this variant. (I) 1206 - This variant has been shown to be paternally inherited (by segregation analysis). Father is unaffected. (I) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign |