ClinVar Genomic variation as it relates to human health
NM_133433.4(NIPBL):c.2479_2480del (p.Arg827fs)
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.
Stars represent the aggregate review status, or the level of review supporting the aggregate germline classification for this VCV record. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the review status. The number of submissions which contribute to this review status is shown in parentheses.
No data submitted for somatic clinical impact
No data submitted for oncogenicity
Variant Details
- Identifiers
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NM_133433.4(NIPBL):c.2479_2480del (p.Arg827fs)
Variation ID: 96336 Accession: VCV000096336.23
- Type and length
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Deletion, 2 bp
- Location
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Cytogenetic: 5p13.2 5: 36985659-36985660 (GRCh38) [ NCBI UCSC ] 5: 36985761-36985762 (GRCh37) [ NCBI UCSC ]
- Timeline in ClinVar
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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 Apr 4, 2013 Feb 14, 2024 Oct 18, 2023 - HGVS
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Nucleotide Protein Molecular
consequenceNM_133433.4:c.2479_2480del MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_597677.2:p.Arg827fs frameshift NM_133433.4:c.2479_2480delAG MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NM_015384.5:c.2479_2480del NP_056199.2:p.Arg827fs frameshift NC_000005.10:g.36985659_36985660del NC_000005.9:g.36985761_36985762del NG_006987.2:g.113777_113778del - Protein change
- R827fs
- Other names
- p.Arg827GlyfsTer2
- Canonical SPDI
- NC_000005.10:36985658:AG:
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Functional
consequence HelpThe effect of the variant on RNA or protein function, based on experimental evidence from submitters.
- protein truncation Variation Ontology [VariO:0015]
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Global minor allele
frequency (GMAF) HelpThe 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.
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Allele frequency
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The frequency of the allele represented by this VCV record.
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Genes
Gene | OMIM | ClinGen Gene Dosage Sensitivity Curation |
Variation Viewer
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Links to Variation Viewer, a genome browser to view variation data from NCBI databases. |
Related variants | ||
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HI score
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The haploinsufficiency score for the gene, curated by ClinGen’s Dosage Sensitivity Curation task team. |
TS score
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The triplosensitivity score for the gene, curated by ClinGen’s Dosage Sensitivity Curation task team. |
Within gene
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The number of variants in ClinVar that are contained within this gene, with a link to view the list of variants. |
All
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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. |
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NIPBL | Sufficient evidence for dosage pathogenicity | Little evidence for dosage pathogenicity |
GRCh38 GRCh37 |
1744 | 1795 |
Conditions - Germline
Condition
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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
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The most recent date that a submitter evaluated this variant for the condition. |
Variation/condition record
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The RCV accession number, with most recent version number, for the variant-condition record, with a link to the RCV web page. |
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Pathogenic (8) |
criteria provided, multiple submitters, no conflicts
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Oct 18, 2023 | RCV000146547.21 | |
Pathogenic (2) |
criteria provided, multiple submitters, no conflicts
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Nov 28, 2022 | RCV000082485.10 |
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
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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. |
More information
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. |
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Pathogenic
(Jun 02, 2020)
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criteria provided, single submitter
Method: clinical testing
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CORNELIA DE LANGE SYNDROME 1
Affected status: yes
Allele origin:
germline
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Rady Children's Institute for Genomic Medicine, Rady Children's Hospital San Diego
Accession: SCV001984850.1
First in ClinVar: Oct 30, 2021 Last updated: Oct 30, 2021 |
Comment:
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 … (more)
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. (less)
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Pathogenic
(Dec 19, 2022)
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criteria provided, single submitter
Method: clinical testing
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Cornelia de Lange syndrome 1
Affected status: unknown
Allele origin:
unknown
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Baylor Genetics
Accession: SCV000747066.2
First in ClinVar: Sep 19, 2018 Last updated: Mar 11, 2023 |
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Pathogenic
(Feb 08, 2013)
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criteria provided, single submitter
Method: clinical testing
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Cornelia de Lange syndrome 1
(Autosomal dominant inheritance)
Affected status: yes
Allele origin:
germline
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Genetic Services Laboratory, University of Chicago
Accession: SCV000193843.1
First in ClinVar: Nov 23, 2014 Last updated: Nov 23, 2014 |
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Pathogenic
(Aug 03, 2012)
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criteria provided, single submitter
Method: clinical testing
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not provided
Affected status: unknown
Allele origin:
germline
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Eurofins Ntd Llc (ga)
Accession: SCV000225096.5
First in ClinVar: Jun 29, 2015 Last updated: Jul 30, 2019 |
Number of individuals with the variant: 1
Sex: mixed
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Pathogenic
(Mar 20, 2018)
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criteria provided, single submitter
Method: clinical testing
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Cornelia de Lange syndrome 1
(Autosomal dominant inheritance)
Affected status: yes
Allele origin:
de novo
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Foundation for Research in Genetics and Endocrinology, FRIGE's Institute of Human Genetics
Accession: SCV001985071.1
First in ClinVar: Nov 05, 2021 Last updated: Nov 05, 2021 |
Comment:
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 … (more)
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. (less)
Clinical Features:
Cleft palate (present) , Mild global developmental delay (present) , Abnormal facial shape (present) , Impaired social interactions (present) , Bilateral ptosis (present) , Low-set … (more)
Cleft palate (present) , Mild global developmental delay (present) , Abnormal facial shape (present) , Impaired social interactions (present) , Bilateral ptosis (present) , Low-set ears (present) , Abnormality of the nose (present) , Short neck (present) , Thick eyebrow (present) (less)
Age: 0-9 years
Sex: male
Ethnicity/Population group: Hindu
Geographic origin: India
Method: DNA was used to perform targeted gene capture using a custom capture kit. Libraries were sequenced to mean >80-100X coverage on Illumina sequencing platform. Sequence obtained were aligned to human references genome using BWA program and analyzed using Picard and GATK-Lite toolkit to identify variants in the targeted genes relevant to clinical indication.
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Pathogenic
(Jul 15, 2021)
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criteria provided, single submitter
Method: clinical testing
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Cornelia de Lange syndrome 1
Affected status: no
Allele origin:
germline
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Genome-Nilou Lab
Accession: SCV002055964.1
First in ClinVar: Jan 12, 2022 Last updated: Jan 12, 2022 |
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Pathogenic
(Oct 18, 2023)
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criteria provided, single submitter
Method: clinical testing
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Cornelia de Lange syndrome 1
Affected status: unknown
Allele origin:
germline
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Invitae
Accession: SCV000934470.6
First in ClinVar: Aug 14, 2019 Last updated: Feb 14, 2024 |
Comment:
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 … (more)
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. (less)
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Pathogenic
(Nov 28, 2022)
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criteria provided, single submitter
Method: clinical testing
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Not Provided
Affected status: yes
Allele origin:
germline
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GeneDx
Accession: SCV000565326.5
First in ClinVar: Mar 24, 2015 Last updated: Dec 11, 2022 |
Comment:
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 … (more)
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) (less)
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Pathogenic
(Oct 01, 2004)
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no assertion criteria provided
Method: literature only
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CORNELIA DE LANGE SYNDROME 1
Affected status: not provided
Allele origin:
germline
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OMIM
Accession: SCV000022385.2
First in ClinVar: Apr 04, 2013 Last updated: Oct 25, 2020 |
Comment on evidence:
In 2 unrelated children with sporadic Cornelia de Lange syndrome (CDLS1; 122470), Gillis et al. (2004) identified a 2-bp deletion in exon 10 of the … (more)
In 2 unrelated children with sporadic Cornelia de Lange syndrome (CDLS1; 122470), Gillis et al. (2004) identified a 2-bp deletion in exon 10 of the NIPBL gene, 2479delAG, resulting in a frameshift and truncation of the protein 2 amino acids downstream. Both children were severely affected in terms of growth and development; however, one had significant limb reduction defects whereas the other did not. (less)
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Pathogenic
(-)
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no assertion criteria provided
Method: research
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Cornelia de Lange syndrome 1
Affected status: yes
Allele origin:
unknown
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Division of Human Genetics, National Health Laboratory Service/University of the Witwatersrand
Accession: SCV002552099.1
First in ClinVar: Jul 27, 2022 Last updated: Jul 27, 2022 |
Number of individuals with the variant: 1
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Germline Functional Evidence
Functional
Help
The functional consequence of the variant, based on experimental evidence and provided by the submitter. consequence |
Method
Help
A brief description of the method used to determine the functional consequence of the variant. A citation for the method is included, when provided by the submitter. |
Result
Help
A brief description of the result of this method for 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. |
More information
Help
This column includes more information supporting functional evidence for the germline classification, including citations, the comment on classification, and detailed evidence provided as observations of the variant by the submitter. |
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protein truncation
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Foundation for Research in Genetics and Endocrinology, FRIGE's Institute of Human Genetics
Accession: SCV001985071.1
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Citations for germline classification of this variant
HelpTitle | Author | Journal | Year | Link |
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Clinical exome sequencing reveals locus heterogeneity and phenotypic variability of cohesinopathies. | Yuan B | Genetics in medicine : official journal of the American College of Medical Genetics | 2019 | PMID: 30158690 |
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 |
Mutations and variants in the cohesion factor genes NIPBL, SMC1A, and SMC3 in a cohort of 30 unrelated patients with Cornelia de Lange syndrome. | Pié J | American journal of medical genetics. Part A | 2010 | PMID: 20358602 |
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 |
Clinical score of 62 Italian patients with Cornelia de Lange syndrome and correlations with the presence and type of NIPBL mutation. | Selicorni A | Clinical genetics | 2007 | PMID: 17661813 |
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 rs398124465 ...
HelpRecord last updated Feb 20, 2024
This date represents the last time this VCV record was updated. The update may be due to an update to one of the included submitted records (SCVs), or due to an update that ClinVar made to the variant such as adding HGVS expressions or a rs number. So this date may be different from the date of the “most recent submission” reported at the top of this page.