VCV000099920.22 - ClinVar

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

Germline

Classification

criteria provided, multiple submitters, no conflicts. Learn more about how ClinVar calculates review status.

Pathogenic
Pathogenic (6)

6 out of 7 submissions contributed to this classification

The aggregate germline classification for this variant, typically for a monogenic or Mendelian disorder as in the ACMG/AMP guidelines, or for response to a drug. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the aggregate classification.

Somatic

No data submitted for somatic clinical impact

Somatic

No data submitted for oncogenicity

Variant Details

Identifiers

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

Variation ID: 99920 Accession: VCV000099920.22

Type and length

single nucleotide variant, 1 bp

Location

Cytogenetic: 5p13.2 5: 36955540 (GRCh38) [ NCBI UCSC ] 5: 36955642 (GRCh37) [ NCBI UCSC ]

Timeline in ClinVar

	First in ClinVar Help The date this variant first appeared in ClinVar with each type of classification.	Last submission Help The date of the most recent submission for each type of classification for this variant.	Last evaluated Help The most recent date that a submitter evaluated this variant for each type of classification.
Germline	Nov 23, 2014	Sep 22, 2026	Mar 8, 2025

HGVS

Nucleotide	Protein	Molecular consequence
NM_133433.4:c.133C>T MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.	NP_597677.2:p.Arg45Ter	nonsense
NM_015384.5:c.133C>T	NP_056199.2:p.Arg45Ter	nonsense
NC_000005.10:g.36955540C>T
NC_000005.9:g.36955642C>T
NG_006987.2:g.83658C>T

... more HGVS ... less HGVS

Protein change

R45*

Other names

Canonical SPDI

NC_000005.10:36955539:C:T

Global minor allele frequency (GMAF) Help The global minor allele frequency calculated by the 1000 Genomes Project. The minor allele at this location is indicated in parentheses and may be different from the allele represented by this VCV record.

Allele frequency Help The frequency of the allele represented by this VCV record.

Links

ClinGen: CA267522 dbSNP: rs80358367 VarSome

Genes

Gene	OMIM	ClinGen Gene Dosage Sensitivity Curation		Variation Viewer Help Links to Variation Viewer, a genome browser to view variation data from NCBI databases.	Related variants
Gene	OMIM	HI score Help The haploinsufficiency score for the gene, curated by ClinGen’s Dosage Sensitivity Curation task team.	TS score Help The triplosensitivity score for the gene, curated by ClinGen’s Dosage Sensitivity Curation task team.		Within gene Help The number of variants in ClinVar that are contained within this gene, with a link to view the list of variants.	All Help The number of variants in ClinVar for this gene, including smaller variants within the gene and larger CNVs that overlap or fully contain the gene.
NIPBL		Sufficient evidence for dosage pathogenicity	Little evidence for dosage pathogenicity	GRCh38 GRCh37	2568	2629

Conditions - Germline

Condition Help The condition for this variant-condition (RCV) record in ClinVar.	Classification Help The aggregate germline classification for this variant-condition (RCV) record in ClinVar. The number of submissions that contribute to this aggregate classification is shown in parentheses. (# of submissions)	Review status Help The aggregate review status for this variant-condition (RCV) record in ClinVar. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the review status.	Last evaluated Help The most recent date that a submitter evaluated this variant for the condition.	Variation/condition record Help The RCV accession number, with most recent version number, for the variant-condition record, with a link to the RCV web page.
Cornelia de Lange syndrome 1	Pathogenic (3)	criteria provided, multiple submitters, no conflicts	Mar 8, 2025	RCV000086366.18
not provided	Pathogenic (2)	criteria provided, multiple submitters, no conflicts	Apr 4, 2024	RCV000724758.8
NIPBL-related disorder	Pathogenic (2)	criteria provided, single submitter	May 31, 2022	RCV003935082.3

Submissions - Germline

Classification Help The submitted germline classification for each SCV record. (Last evaluated)	Review status Help Stars represent the review status, or the level of review supporting the submitted (SCV) record. This value is calculated by NCBI based on data from the submitter. Read our rules for calculating the review status. This column also includes a link to the submitter’s assertion criteria if provided, and the collection method. (Assertion criteria)	Condition Help The condition for the classification, provided by the submitter for this submitted (SCV) record. This column also includes the affected status and allele origin of individuals observed with this variant.	Submitter Help The submitting organization for this submitted (SCV) record. This column also includes the SCV accession and version number, the date this SCV first appeared in ClinVar, and the date that this SCV was last updated in ClinVar.	Expand all rows Collapse all rows Help This column includes more information supporting the classification, including citations, the comment on classification, and detailed evidence provided as observations of the variant by the submitter.
Pathogenic (Feb 08, 2013) C Contributing to aggregate classification	criteria provided, single submitter (ACMG Guidelines, 2007)	Cornelia de Lange syndrome 1 (Autosomal dominant inheritance)	Genetic Services Laboratory, University of Chicago Accession: SCV000193809.1 First in ClinVar: Nov 23, 2014 Last updated: Nov 23, 2014	Observation: 1 Collection method: clinical testing Allele origin: germline Affected status: yes Observation 1 Collection method: clinical testing Allele origin: germline Affected status: yes

Pathogenic (Apr 15, 2015) C Contributing to aggregate classification	criteria provided, single submitter (EGL Classification Definitions 2015)	not provided	Eurofins Ntd Llc (ga) Accession: SCV000229252.6 First in ClinVar: Jun 29, 2015 Last updated: Apr 13, 2025	Publications: PubMed (1) PubMed: 20824775 Other databases http://www.egl-eurofins.com/emvc… http://www.egl-eurofins.com/emvclass/emvclass.php?approved_symbol=NIPBL Observation: 1 Collection method: clinical testing Allele origin: germline Affected status: unknown more Observation 1 Collection method: clinical testing Allele origin: germline Affected status: unknown Number of individuals with the variant: 1 Zygosity: 1 Single Heterozygote Sex: mixed

Pathogenic (Jul 15, 2021) C Contributing to aggregate classification	criteria provided, single submitter (ACMG Guidelines, 2015)	Cornelia de Lange syndrome 1	Genome-Nilou Lab Accession: SCV002055959.1 First in ClinVar: Jan 12, 2022 Last updated: Jan 12, 2022	Observation: 1 Collection method: clinical testing Allele origin: germline Affected status: no Observation 1 Collection method: clinical testing Allele origin: germline Affected status: no

Pathogenic (Apr 04, 2024) C Contributing to aggregate classification	criteria provided, single submitter (GeneDx Variant Classification Process June 2021)	not provided	GeneDx Accession: SCV000890255.2 First in ClinVar: Mar 19, 2019 Last updated: Sep 16, 2024	Comment: show Nonsense 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 in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 20824775, 34326454, 32033219, 37377026) (less) Observation: 1 Collection method: clinical testing Allele origin: germline Affected status: yes Observation 1 Collection method: clinical testing Allele origin: germline Affected status: yes

Pathogenic (Mar 08, 2025) C Contributing to aggregate classification	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Cornelia de Lange syndrome 1	Labcorp Genetics (formerly Invitae), Labcorp Accession: SCV000775588.6 First in ClinVar: Jun 29, 2015 Last updated: Mar 07, 2026	Publications: PubMed (5) PubMed: 15318302‚ 19763162‚ 20824775‚ 23505322‚ 29995837 Comment: show 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). Invitae Evidence Modeling of clinical and family history, age, sex, and reported ancestry of multiple individuals with this NIPBL variant has been performed. This variant is expected to be pathogenic with a positive predictive value of at least 99%. This is a validated machine learning model that incorporates the clinical features of 8,969 individuals referred to our laboratory for NIPBL testing. ClinVar contains an entry for this variant (Variation ID: 99920). For these reasons, this variant has been classified as Pathogenic. (less) Observation: 1 Collection method: clinical testing Allele origin: germline Affected status: unknown Observation 1 Collection method: clinical testing Allele origin: germline Affected status: unknown

Pathogenic (May 31, 2022) C Contributing to aggregate classification	criteria provided, single submitter (ACMG Guidelines, 2015)	NIPBL-related disorders	Blueprint Genetics Accession: SCV007958412.1 First in ClinVar: Sep 22, 2026 Last updated: Sep 22, 2026	Observation: 1 Collection method: clinical testing Allele origin: germline Affected status: yes more Observation 1 Collection method: clinical testing Allele origin: germline Affected status: yes Number of individuals with the variant: 1 Test name: Cornelia de Lange Syndrome Panel

Pathogenic (Nov 10, 2023) N Not contributing to aggregate classification	no assertion criteria provided	NIPBL-related condition	PreventionGenetics, part of Exact Sciences Accession: SCV004752555.2 First in ClinVar: Mar 16, 2024 Last updated: Oct 08, 2024	Comment: show 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. (less) Observation: 1 Collection method: clinical testing Allele origin: germline Affected status: unknown Observation 1 Collection method: clinical testing Allele origin: germline Affected status: unknown

Comment:

Nonsense 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 in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 20824775, 34326454, 32033219, 37377026)

Comment:

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). Invitae Evidence Modeling of clinical and family history, age, sex, and reported ancestry of multiple individuals with this NIPBL variant has been performed. This variant is expected to be pathogenic with a positive predictive value of at least 99%. This is a validated machine learning model that incorporates the clinical features of 8,969 individuals referred to our laboratory for NIPBL testing. ClinVar contains an entry for this variant (Variation ID: 99920). For these reasons, this variant has been classified as Pathogenic.

Comment:

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.

Citations for germline classification of this variant

Title	Author	Journal	Year	Link
Diagnosis and management of Cornelia de Lange syndrome: first international consensus statement.	Kline AD	Nature reviews. Genetics	2018	PMID: 29995837
High rate of mosaicism in individuals with Cornelia de Lange syndrome.	Huisman SA	Journal of medical genetics	2013	PMID: 23505322
Development of NIPBL locus-specific database using LOVD: from novel mutations to further genotype-phenotype correlations in Cornelia de Lange Syndrome.	Oliveira J	Human mutation	2010	PMID: 20824775
Multiple organ system defects and transcriptional dysregulation in the Nipbl(+/-) mouse, a model of Cornelia de Lange Syndrome.	Kawauchi S	PLoS genetics	2009	PMID: 19763162
NIPBL mutational analysis in 120 individuals with Cornelia de Lange syndrome and evaluation of genotype-phenotype correlations.	Gillis LA	American journal of human genetics	2004	PMID: 15318302
http://www.egl-eurofins.com/emvclass/emvclass.php?approved_symbol=NIPBL	-	-	-	-

Text-mined citations for rs80358367 ...

These citations are identified by LitVar using the rs number, so they may include citations for more than one variant at this location. Please review the LitVar results carefully for your variant of interest.

Record last updated Sep 27, 2026