Submissions for variant NM_133433.4(NIPBL):c.5329-15A>G

dbSNP: rs587783968

Total submissions: 9

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Genetic Services Laboratory, University of Chicago	RCV001582611	SCV000193941	pathogenic	not provided	2020-10-30	criteria provided, single submitter	clinical testing
Invitae	RCV000795862	SCV000935340	pathogenic	Cornelia de Lange syndrome 1	2023-07-20	criteria provided, single submitter	clinical testing	For these reasons, this variant has been classified as Pathogenic. Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. ClinVar contains an entry for this variant (Variation ID: 159142). This variant has been observed in individual(s) with Cornelia de Lange syndrome (PMID: 26701315, 26925417). In at least one individual the variant was observed to be de novo. This variant is not present in population databases (gnomAD no frequency). This sequence change falls in intron 27 of the NIPBL gene. It does not directly change the encoded amino acid sequence of the NIPBL protein.
GeneDx	RCV001582611	SCV001819552	pathogenic	not provided	2022-10-19	criteria provided, single submitter	clinical testing	Published functional studies demonstrate that c.5329-15A>G results in in-frame skipping of exon 28 and has a damaging effect on the gene product (Nizon et al., 2016; Teresa-Rodrigo et al., 2016; Masciadri et al., 2018); Not observed at significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 27164022, 26701315, 26925417, 30538663, 34717699, 35183220)
Genome-Nilou Lab	RCV000795862	SCV002054153	pathogenic	Cornelia de Lange syndrome 1	2021-07-15	criteria provided, single submitter	clinical testing
Mendelics	RCV000795862	SCV002517798	pathogenic	Cornelia de Lange syndrome 1	2022-05-04	criteria provided, single submitter	clinical testing
3billion	RCV000795862	SCV002573294	pathogenic	Cornelia de Lange syndrome 1	2022-09-01	criteria provided, single submitter	clinical testing	The variant is not observed in the gnomAD v2.1.1 dataset. Functional studies provide strong evidence of the variant having a damaging effect on the gene or gene product (PMID: 26925417). The variant has been observed in multiple (>3) similarly affected unrelated individuals (PMID: 26925417). The variant has been reported to co-segregate with the disease in at least 3 similarly affected relatives/individuals in the same family or similarly affected unrelated families (PMID: 26925417). The variant has been reported at least twice as pathogenic with clinical assertions and evidence for the classification (ClinVar ID: VCV000159142). Therefore, this variant is classified as Pathogenic according to the recommendation of ACMG/AMP guideline.
Ambry Genetics	RCV002515967	SCV003536981	pathogenic	Inborn genetic diseases	2022-09-19	criteria provided, single submitter	clinical testing	The c.5329-15A>G intronic alteration consists of an A to G substitution 15 nucleotides before exon 28 (coding exon 27) of the NIPBL gene. This variant was not reported in population-based cohorts in the Genome Aggregation Database (gnomAD). This variant has been reported in multiple individuals with features consistent with Cornelia de Lange syndrome (Nizon, 2016; Teresa-Rodrigo, 2016). This nucleotide position is poorly conserved in available vertebrate species. RNA studies have demonstrated that this alteration results in abnormal splicing (Nizon, 2016; Teresa-Rodrigo, 2016). In silico splice site analysis predicts that this alteration may weaken the native splice acceptor site. Based on the available evidence, this alteration is classified as pathogenic.
PreventionGenetics, part of Exact Sciences	RCV003415975	SCV004113400	pathogenic	NIPBL-related condition	2022-12-13	criteria provided, single submitter	clinical testing	The NIPBL c.5329-15A>G variant is predicted to interfere with splicing. This variant has been previously reported in individuals with Cornelia de Lange syndrome or neurodevelopmental disorders (Teresa-Rodrigo et al. 2016. PubMed ID: 26925417; Nizon et al. 2016. PubMed ID: 26701315; Table 3, Pablo et al. 2021. PubMed ID: 34717699; Álvarez-Mora et al. 2022. PubMed ID: 35183220). Functional studies have found that the presence of this variant results in the skipping of exon 28, with a shorter protein product which retains its reading frame (Teresa-Rodrigo et al. 2016. PubMed ID: 26925417). This variant has not been reported in a large polulation database (http://gnomad.broadinstitute.org), indicating this variant is rare. This variant is interpreted as likely pathogenic.
Bioscientia Institut fuer Medizinische Diagnostik GmbH, Sonic Healthcare	RCV000795862	SCV001192590	pathogenic	Cornelia de Lange syndrome 1	2019-06-25	no assertion criteria provided	clinical testing