VCV000159223.29 - ClinVar

NM_133433.4(NIPBL):c.7168G>A (p.Ala2390Thr)

Germline

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.

(11)

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.

Pathogenic/Likely pathogenic

criteria provided, multiple submitters, no conflicts

Somatic

No data submitted for somatic clinical impact

Somatic

No data submitted for oncogenicity

Variant Details

Identifiers

NM_133433.4(NIPBL):c.7168G>A (p.Ala2390Thr)

Variation ID: 159223 Accession: VCV000159223.29

Type and length

single nucleotide variant, 1 bp

Location

Cytogenetic: 5p13.2 5: 37052471 (GRCh38) [ NCBI UCSC ] 5: 37052573 (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	May 1, 2024	Jun 14, 2023

HGVS

Nucleotide	Protein	Molecular consequence
NM_133433.4:c.7168G>A MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.	NP_597677.2:p.Ala2390Thr	missense
NM_015384.5:c.7168G>A	NP_056199.2:p.Ala2390Thr	missense
NC_000005.10:g.37052471G>A
NC_000005.9:g.37052573G>A
NG_006987.2:g.180589G>A
	Q6KC79:p.Ala2390Thr

... more HGVS ... less HGVS

Protein change

A2390T

Other names

Canonical SPDI

NC_000005.10:37052470:G:A

Functional consequence Help The effect of the variant on RNA or protein function, based on experimental evidence from submitters.

Uncertain function

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: CA272292 UniProtKB: Q6KC79#VAR_021607 dbSNP: rs587784036 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	1812	1866

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/Likely pathogenic (6)	criteria provided, multiple submitters, no conflicts	Apr 9, 2023	RCV000146717.22
not provided	Pathogenic (3)	criteria provided, single submitter	May 5, 2022	RCV000494480.8
NIPBL-related disorder	Likely pathogenic (1)	criteria provided, single submitter	Jun 14, 2023	RCV003407564.4
Inborn genetic diseases	Likely pathogenic (1)	criteria provided, single submitter	Apr 11, 2017	RCV002371984.2

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.	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.
Pathogenic (Feb 08, 2013)	criteria provided, single submitter (ACMG Guidelines, 2007) Method: clinical testing	Cornelia de Lange syndrome 1 (Autosomal dominant inheritance) Affected status: yes Allele origin: germline	Genetic Services Laboratory, University of Chicago Accession: SCV000194033.1 First in ClinVar: Nov 23, 2014 Last updated: Nov 23, 2014
Pathogenic (Nov 28, 2018)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Cornelia de Lange syndrome 1 Affected status: yes Allele origin: de novo	Victorian Clinical Genetics Services, Murdoch Childrens Research Institute Accession: SCV001245029.1 First in ClinVar: May 04, 2020 Last updated: May 04, 2020	Comment: A heterozygous missense variant, NM_133433.3(NIPBL):c.7168G>A, has been identified in exon 42 of 47 of the NIPBL gene. The variant is predicted to result in a … (more) A heterozygous missense variant, NM_133433.3(NIPBL):c.7168G>A, has been identified in exon 42 of 47 of the NIPBL gene. The variant is predicted to result in a minor amino acid change from alanine to threonine at position 2390 of the protein (NP_597677.2(NIPBL):p.(Ala2390Thr)). The alanine residue at this position has very high conservation (100 vertebrates, UCSC), and is located within the Nipped-B_C domain. In silico predictions for this variant are consistently pathogenic (Polyphen, SIFT, CADD, Mutation Taster). The variant is absent in population databases (gnomAD, dbSNP, 1000G), but has previously been reported in patients with Cornelia de Lange syndrome (ClinVar, Gills L. et al. (2004), Huisman S. et al. (2013)). Analysis of parental samples indicated this variant is de novo. Based on the information available at the time of curation, this variant has been classified as PATHOGENIC. (less) Number of individuals with the variant: 1 Clinical Features: Intrauterine growth retardation (present) , Tetralogy of Fallot (present) , Highly arched eyebrow (present) , Smooth philtrum (present) , Micrognathia (present) , Microcephaly (present) Secondary finding: no
Pathogenic (Jul 27, 2018)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Cornelia de Lange syndrome 1 (Autosomal dominant inheritance) Affected status: yes Allele origin: de novo	Foundation for Research in Genetics and Endocrinology, FRIGE's Institute of Human Genetics Accession: SCV001985072.1 First in ClinVar: Nov 05, 2021 Last updated: Nov 05, 2021	Comment: A heterozygous missense variation in exon 42 of the NIPBL gene that results in the amino acid substitution of Threonine for Alanine at codon 2390 … (more) A heterozygous missense variation in exon 42 of the NIPBL gene that results in the amino acid substitution of Threonine for Alanine at codon 2390 was detected. The observed variant c.7168G>A (p.Ala2390Thr) has not been observed in the 1000 genomes and gnomAD databases. The in silico prediction of the variant is benign by PolyPhen-2 (HumDiv), SIFT, LRT and MutationTaster2. The reference codon is conserved across species Segregation analysis showed the variant to be of de novo origin. In summary, the variant meets our criteria to be classified as pathogenic. (less) Clinical Features: Oligohydramnios (present) , Fetal distress (present) , Premature birth (present) , Small for gestational age (present) , Brachycephaly (present) , Small fontanelle (present) , Short … (more) Oligohydramnios (present) , Fetal distress (present) , Premature birth (present) , Small for gestational age (present) , Brachycephaly (present) , Small fontanelle (present) , Short nose (present) , Smooth philtrum (present) , Upturned corners of mouth (present) , Thin vermilion border (present) , Narrow mouth (present) , Micrognathia (present) (less) Age: 0-9 years Sex: female 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.
Likely pathogenic (Jul 15, 2021)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Cornelia de Lange syndrome 1 Affected status: no Allele origin: germline	Genome-Nilou Lab Accession: SCV002054161.1 First in ClinVar: Jan 12, 2022 Last updated: Jan 12, 2022
Pathogenic (May 05, 2022)	criteria provided, single submitter (GeneDx Variant Classification Process June 2021) Method: clinical testing	Not Provided Affected status: yes Allele origin: germline	GeneDx Accession: SCV000582781.6 First in ClinVar: Jul 02, 2017 Last updated: Mar 04, 2023	Comment: Published functional studies demonstrate a damaging effect with impaired ATPase and DNA loop extrusion activities of cohesin (Panarotto et al., 2022); Not observed at significant … (more) Published functional studies demonstrate a damaging effect with impaired ATPase and DNA loop extrusion activities of cohesin (Panarotto et al., 2022); Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 15318302, 35476527, 23505322, 32573669, 34326454) (less)
Pathogenic (Apr 09, 2023)	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015)) Method: clinical testing	Cornelia de Lange syndrome 1 Affected status: unknown Allele origin: germline	Labcorp Genetics (formerly Invitae), Labcorp Accession: SCV000944779.6 First in ClinVar: Aug 14, 2019 Last updated: Feb 14, 2024	Publications: PubMed (2) PubMed: 15318302‚ 23505322 Comment: For these reasons, this variant has been classified as Pathogenic. Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, … (more) For these reasons, this variant has been classified as Pathogenic. Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is expected to disrupt NIPBL protein function. ClinVar contains an entry for this variant (Variation ID: 159223). This missense change has been observed in individual(s) with classical Cornelia de Lange syndrome and mild Cornelia de Lange syndrome (PMID: 15318302, 23505322; Invitae). 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 replaces alanine, which is neutral and non-polar, with threonine, which is neutral and polar, at codon 2390 of the NIPBL protein (p.Ala2390Thr). (less)
Likely pathogenic (Jun 14, 2023)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	NIPBL-related condition Affected status: unknown Allele origin: germline	PreventionGenetics, part of Exact Sciences Accession: SCV004107786.1 First in ClinVar: Nov 20, 2023 Last updated: Nov 20, 2023	Comment: The NIPBL c.7168G>A variant is predicted to result in the amino acid substitution p.Ala2390Thr. This variant was previously reported in individuals with a clinical diagnosis … (more) The NIPBL c.7168G>A variant is predicted to result in the amino acid substitution p.Ala2390Thr. This variant was previously reported in individuals with a clinical diagnosis of Cornelia de Lange syndrome (CdLS) (Table 1, patient 067P in Figure 1, Gillis et al. 2004. PubMed ID: 15318302), reported as de novo (Table S1, Mannini et al. 2013. PubMed ID: 24038889), or mosaic finding (Huisman et al. 2013. PubMed ID: 23505322). This variant was also identified in a two-day old critically ill infant presenting with intrauterine growth retardation, tetralogy of Fallot, highly arched eyebrow, smooth philtrum, micrognathia and microcephaly (Table e3, Lunke et al. 2020. PubMed ID: 32573669). This variant has not been reported in a large population database (http://gnomad.broadinstitute.org), indicating this variant is rare. This variant is interpreted as likely pathogenic. (less)
Likely pathogenic (Jan 14, 2022)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Cornelia de Lange syndrome 1 Affected status: unknown Allele origin: germline	Revvity Omics, Revvity Accession: SCV003815065.2 First in ClinVar: Mar 04, 2023 Last updated: Feb 04, 2024
Likely pathogenic (Apr 11, 2017)	criteria provided, single submitter (Ambry Variant Classification Scheme 2023) Method: clinical testing	Inborn genetic diseases Affected status: unknown Allele origin: germline	Ambry Genetics Accession: SCV002662783.2 First in ClinVar: Nov 29, 2022 Last updated: May 01, 2024	Publications: PubMed (3) PubMed: 15318302‚ 23505322‚ 24038889 Comment: The p.A2390T variant (also known as c.7168G>A), located in coding exon 41 of the NIPBL gene, results from a G to A substitution at nucleotide … (more) The p.A2390T variant (also known as c.7168G>A), located in coding exon 41 of the NIPBL gene, results from a G to A substitution at nucleotide position 7168. The alanine at codon 2390 is replaced by threonine, an amino acid with similar properties. This variant was identified in 2 individuals with Cornelia de Lange syndrome. In one individual, this alteration occurred de novo, although paternity was not confirmed (Gillis LA et al. Am. J. Hum. Genet., 2004 Oct;75:610-23). The other individual was mosaic for this alteration; it was detected in buccal cells, but was absent in lymphocytes (Mannini L et al. Hum. Mutat., 2013 Dec;34:1589-96). This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. Based on the majority of available evidence to date, this variant is likely to be pathogenic. (less)
Pathogenic (-)	no assertion criteria provided Method: clinical testing	not provided Affected status: yes Allele origin: germline	Genome Diagnostics Laboratory, Amsterdam University Medical Center Additional submitter: Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen Study: VKGL Data-share Consensus Accession: SCV001807283.2 First in ClinVar: Aug 25, 2021 Last updated: Oct 16, 2021
Pathogenic (-)	no assertion criteria provided Method: clinical testing	not provided Affected status: yes Allele origin: germline	Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+ Additional submitter: Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen Study: VKGL Data-share Consensus Accession: SCV001953587.1 First in ClinVar: Oct 02, 2021 Last updated: Oct 02, 2021
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Comment:

A heterozygous missense variant, NM_133433.3(NIPBL):c.7168G>A, has been identified in exon 42 of 47 of the NIPBL gene. The variant is predicted to result in a minor amino acid change from alanine to threonine at position 2390 of the protein (NP_597677.2(NIPBL):p.(Ala2390Thr)). The alanine residue at this position has very high conservation (100 vertebrates, UCSC), and is located within the Nipped-B_C domain. In silico predictions for this variant are consistently pathogenic (Polyphen, SIFT, CADD, Mutation Taster). The variant is absent in population databases (gnomAD, dbSNP, 1000G), but has previously been reported in patients with Cornelia de Lange syndrome (ClinVar, Gills L. et al. (2004), Huisman S. et al. (2013)). Analysis of parental samples indicated this variant is de novo. Based on the information available at the time of curation, this variant has been classified as PATHOGENIC.

Comment:

A heterozygous missense variation in exon 42 of the NIPBL gene that results in the amino acid substitution of Threonine for Alanine at codon 2390 was detected. The observed variant c.7168G>A (p.Ala2390Thr) has not been observed in the 1000 genomes and gnomAD databases. The in silico prediction of the variant is benign by PolyPhen-2 (HumDiv), SIFT, LRT and MutationTaster2. The reference codon is conserved across species Segregation analysis showed the variant to be of de novo origin. In summary, the variant meets our criteria to be classified as pathogenic.

Comment:

Published functional studies demonstrate a damaging effect with impaired ATPase and DNA loop extrusion activities of cohesin (Panarotto et al., 2022); Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 15318302, 35476527, 23505322, 32573669, 34326454)

Comment:

For these reasons, this variant has been classified as Pathogenic. Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is expected to disrupt NIPBL protein function. ClinVar contains an entry for this variant (Variation ID: 159223). This missense change has been observed in individual(s) with classical Cornelia de Lange syndrome and mild Cornelia de Lange syndrome (PMID: 15318302, 23505322; Invitae). 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 replaces alanine, which is neutral and non-polar, with threonine, which is neutral and polar, at codon 2390 of the NIPBL protein (p.Ala2390Thr).

Comment:

The NIPBL c.7168G>A variant is predicted to result in the amino acid substitution p.Ala2390Thr. This variant was previously reported in individuals with a clinical diagnosis of Cornelia de Lange syndrome (CdLS) (Table 1, patient 067P in Figure 1, Gillis et al. 2004. PubMed ID: 15318302), reported as de novo (Table S1, Mannini et al. 2013. PubMed ID: 24038889), or mosaic finding (Huisman et al. 2013. PubMed ID: 23505322). This variant was also identified in a two-day old critically ill infant presenting with intrauterine growth retardation, tetralogy of Fallot, highly arched eyebrow, smooth philtrum, micrognathia and microcephaly (Table e3, Lunke et al. 2020. PubMed ID: 32573669). This variant has not been reported in a large population database (http://gnomad.broadinstitute.org), indicating this variant is rare. This variant is interpreted as likely pathogenic.

Comment:

The p.A2390T variant (also known as c.7168G>A), located in coding exon 41 of the NIPBL gene, results from a G to A substitution at nucleotide position 7168. The alanine at codon 2390 is replaced by threonine, an amino acid with similar properties. This variant was identified in 2 individuals with Cornelia de Lange syndrome. In one individual, this alteration occurred de novo, although paternity was not confirmed (Gillis LA et al. Am. J. Hum. Genet., 2004 Oct;75:610-23). The other individual was mosaic for this alteration; it was detected in buccal cells, but was absent in lymphocytes (Mannini L et al. Hum. Mutat., 2013 Dec;34:1589-96). This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. Based on the majority of available evidence to date, this variant is likely to be pathogenic.

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.
Uncertain function			Foundation for Research in Genetics and Endocrinology, FRIGE's Institute of Human Genetics Accession: SCV001985072.1

Comment:

Citations for germline classification of this variant

Title	Author	Journal	Year	Link
Mutation spectrum and genotype-phenotype correlation in Cornelia de Lange syndrome.	Mannini L	Human mutation	2013	PMID: 24038889
High rate of mosaicism in individuals with Cornelia de Lange syndrome.	Huisman SA	Journal of medical genetics	2013	PMID: 23505322
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

Text-mined citations for rs587784036 ...

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 29, 2024

ClinVar Genomic variation as it relates to human health

NM_133433.4(NIPBL):c.7168G>A (p.Ala2390Thr)

Variant Details

Genes

Conditions - Germline

Submissions - Germline

Germline Functional Evidence

Citations for germline classification of this variant

Text-mined citations for rs587784036 ...