Submissions for variant NM_133433.4(NIPBL):c.2479_2480del (p.Arg827fs)

dbSNP: rs398124465

Total submissions: 10

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Genetic Services Laboratory, University of Chicago	RCV000146547	SCV000193843	pathogenic	Cornelia de Lange syndrome 1	2013-02-08	criteria provided, single submitter	clinical testing
Eurofins Ntd Llc (ga)	RCV000082485	SCV000225096	pathogenic	not provided	2012-08-03	criteria provided, single submitter	clinical testing
GeneDx	RCV000082485	SCV000565326	pathogenic	not provided	2022-11-28	criteria provided, single submitter	clinical testing	Frameshift variant predicted to result in protein truncation or nonsense mediated decay in a gene for which loss of function is a known mechanism of disease; Not observed at significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 23760082, 16236812, 30158690, 36041635, 31337854, 31157197, 15318302, 20358602)
Baylor Genetics	RCV000146547	SCV000747066	pathogenic	Cornelia de Lange syndrome 1	2022-12-19	criteria provided, single submitter	clinical testing
Invitae	RCV000146547	SCV000934470	pathogenic	Cornelia de Lange syndrome 1	2023-10-18	criteria provided, single submitter	clinical testing	This sequence change creates a premature translational stop signal (p.Arg827Glyfs*2) 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: 15318302, 17661813, 20358602, 20824775). ClinVar contains an entry for this variant (Variation ID: 96336). For these reasons, this variant has been classified as Pathogenic.
Rady Children's Institute for Genomic Medicine, Rady Children's Hospital San Diego	RCV000146547	SCV001984850	pathogenic	Cornelia de Lange syndrome 1	2020-06-02	criteria provided, single submitter	clinical testing	This frameshifting variant in exon 10 of 47 introduces a premature stop codon and is therefore predicted to result in loss of normal protein function through either protein truncation or nonsense-mediated mRNA decay (NMD). This variant has been previously reported as a heterozygous change in multiple unrelated individuals with Cornelia de Lange Syndrome (CdLS, PMID: 15318302, 17661813, 20358602, 20824775, 30158690, 31157197). Cells lines from a CdLS patient carrying this variant exhibited chromatin decompaction (PMID: 23760082). In addition, gene expression studies on human induced pluripotent stem cells and cardiomyocytes derived in-vitro from a carrier of this variant identified altered expression of genes involved in multiple cellular processes and normal heart development (PMID: 29348408). It is absent from the gnomAD population database and thus is presumed to be rare. Analysis of the parental samples was negative for the variant, indicating this variant likely occurred as a de novo event. Based on the available evidence, the c.2479_2480del (p.Arg827GlyfsTer2) variant is classified as Pathogenic.
Foundation for Research in Genetics and Endocrinology, FRIGE's Institute of Human Genetics	RCV000146547	SCV001985071	pathogenic	Cornelia de Lange syndrome 1	2018-03-20	criteria provided, single submitter	clinical testing	A heterozygous frameshift variation in exon 10 of the NIPBL gene that results in the termination of amino acid 2 codons downstream of Glycine at codon 827 was detected. The observed variant c.2479_2480delAG (p.Arg827GlyfsTer2) has not been reported in the 1000 gemomes, ExAC database. The in-silico prediction of the variant is disease causing by MutationTaster2. The reference codon is conserved across species. The segregation analysis showed this variation to be de novo in origin. In summary, the variant meets our criteria to be classified as a pathogenic variant.
Genome-Nilou Lab	RCV000146547	SCV002055964	pathogenic	Cornelia de Lange syndrome 1	2021-07-15	criteria provided, single submitter	clinical testing
OMIM	RCV000146547	SCV000022385	pathogenic	Cornelia de Lange syndrome 1	2004-10-01	no assertion criteria provided	literature only
Division of Human Genetics, National Health Laboratory Service/University of the Witwatersrand	RCV000146547	SCV002552099	pathogenic	Cornelia de Lange syndrome 1		no assertion criteria provided	research