Total submissions: 5
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| Genetic Services Laboratory, |
RCV000146704 | SCV000194020 | pathogenic | Cornelia de Lange syndrome 1 | 2013-08-27 | criteria provided, single submitter | clinical testing | |
| Invitae | RCV000146704 | SCV000827404 | pathogenic | Cornelia de Lange syndrome 1 | 2020-06-02 | criteria provided, single submitter | clinical testing | For these reasons, this variant has been classified as Pathogenic. A different missense substitution at this codon (p.Arg2298His) has been determined to be pathogenic (PMID: 15318302, 16100726, 26725122). This suggests that the arginine residue is critical for NIPBL protein function and that other missense substitutions at this position may also be pathogenic. Algorithms developed to predict the effect of missense changes on protein structure and function do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Probably Damaging"; Align-GVGD: "Class C0"). This variant has been reported in individuals affected with Cornelia de Lange syndrome (PMID: 15318302) and has been reported to arise de novo in at least 2 affected individuals (PMID: 23254390, 17661813). ClinVar contains an entry for this variant (Variation ID: 159210). This variant is not present in population databases (ExAC no frequency). This sequence change replaces arginine with cysteine at codon 2298 of the NIPBL protein (p.Arg2298Cys). The arginine residue is moderately conserved and there is a large physicochemical difference between arginine and cysteine. |
| Gene |
RCV001552677 | SCV001773411 | pathogenic | not provided | 2021-06-16 | criteria provided, single submitter | clinical testing | Not observed at significant frequency in large population cohorts (Lek et al., 2016); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 34035299, 27535533, 17661813, 20824775, 16819604, 24038889, 17640042, 23254390, 15318302) |
| Genome- |
RCV000146704 | SCV002054159 | pathogenic | Cornelia de Lange syndrome 1 | 2021-07-15 | criteria provided, single submitter | clinical testing | |
| Victorian Clinical Genetics Services, |
RCV000146704 | SCV002769488 | pathogenic | Cornelia de Lange syndrome 1 | 2022-09-02 | criteria provided, single submitter | clinical testing | Based on the classification scheme VCGS_Germline_v1.3.4, this variant is classified as Pathogenic. 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 (MIM#122470). (I) 0107 - This gene is associated with autosomal dominant disease. (I) 0200 - Variant is predicted to result in a missense amino acid change from arginine to cysteine. (I) 0251 - This variant is heterozygous. (I) 0301 - Variant is absent from gnomAD (both v2 and v3). (SP) 0501 - Missense variant consistently predicted to be damaging by multiple in silico tools or highly conserved with a major amino acid change. (SP) 0600 - Variant is located in the annotated sister chromatid cohesion C-terminus domain (DECIPHER). (I) 0702 - Other missense variants comparable to the one identified in this case have strong previous evidence for pathogenicity. p.(Arg2298His) and p.(Arg2298Gly) have been classified as pathogenic and likely pathogenic by clinical laboratories in ClinVar. (SP) 0801 - This variant has strong previous evidence of pathogenicity in unrelated individuals. This variant has been classified as pathogenic by multiple clinical laboratories in ClinVar, and has been observed in several individuals with Cornelia de Lange syndrome including at least two de novo cases (DECIPHER, PMIDs: 23254390, 35769956). (SP) 1208 - Inheritance information for this variant is not currently available in this individual. (I) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign |