Submissions for variant NM_133433.4(NIPBL):c.133C>T (p.Arg45Ter)

dbSNP: rs80358367

Total submissions: 6

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Genetic Services Laboratory, University of Chicago	RCV000086366	SCV000193809	pathogenic	Cornelia de Lange syndrome 1	2013-02-08	criteria provided, single submitter	clinical testing
Eurofins Ntd Llc (ga)	RCV000724758	SCV000229252	pathogenic	not provided	2015-04-15	criteria provided, single submitter	clinical testing
Invitae	RCV000086366	SCV000775588	pathogenic	Cornelia de Lange syndrome 1	2024-01-03	criteria provided, single submitter	clinical testing	This sequence change creates a premature translational stop signal (p.Arg45*) in the NIPBL gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in NIPBL are known to be pathogenic (PMID: 15318302, 19763162, 23505322, 29995837). This variant is not present in population databases (gnomAD no frequency). This premature translational stop signal has been observed in individuals with Cornelia de Lange syndrome (PMID: 20824775). ClinVar contains an entry for this variant (Variation ID: 99920). For these reasons, this variant has been classified as Pathogenic.
GeneDx	RCV000724758	SCV000890255	pathogenic	not provided	2018-12-19	criteria provided, single submitter	clinical testing	The R45X nonsense variant in the NIPBL gene has been reported previously in association with Cornelia de Lange syndrome (Oliveira et al., 2010; Landrum et al., 2016). This pathogenic variant is predicted to cause loss of normal protein function either through protein truncation or nonsense-mediated mRNA decay. The R45X variant is not observed in large population cohorts (Lek et al., 2016). Therefore, R45X is considered a pathogenic variant.
Genome-Nilou Lab	RCV000086366	SCV002055959	pathogenic	Cornelia de Lange syndrome 1	2021-07-15	criteria provided, single submitter	clinical testing
PreventionGenetics, part of Exact Sciences	RCV003935082	SCV004752555	pathogenic	NIPBL-related condition	2023-11-10	criteria provided, single submitter	clinical testing	The NIPBL c.133C>T variant is predicted to result in premature protein termination (p.Arg45*). This variant was reported in two individuals with Cornelia de Lange syndrome (Oliveira et al. 2010. PubMed ID: 20824775; Table S1, Levy et al. 2022. PubMed ID: 35904121). This variant has not been reported in a large population database (http://gnomad.broadinstitute.org), indicating this variant is rare. Nonsense variants in NIPBL are expected to be pathogenic. This variant is interpreted as pathogenic.