NM_133433.4(NIPBL):c.7012G>C (p.Ala2338Pro) AND Cornelia de Lange syndrome 1

Germline classification:: Pathogenic/Likely pathogenic (3 submissions)
Last evaluated:: Jan 7, 2024
Review status:: 2 stars out of maximum of 4 stars
criteria provided, multiple submitters, no conflicts

Somatic classification of clinical impact:: None
Review status:: (0/4) 0 stars out of maximum of 4 stars
no assertion criteria provided

Somatic classification of oncogenicity:: None
Review status:: (0/4) 0 stars out of maximum of 4 stars
no assertion criteria provided

Record status:: current
Accession:: RCV000146711.12

Allele description [Variation Report for NM_133433.4(NIPBL):c.7012G>C (p.Ala2338Pro)]

NM_133433.4(NIPBL):c.7012G>C (p.Ala2338Pro)

Gene:

NIPBL:NIPBL cohesin loading factor [Gene - OMIM - HGNC]

Variant type:

single nucleotide variant

Cytogenetic location:

5p13.2

Genomic location:

Preferred name:

NM_133433.4(NIPBL):c.7012G>C (p.Ala2338Pro)

HGVS:

NC_000005.10:g.37051836G>C
NG_006987.2:g.179954G>C
NM_015384.5:c.7012G>C
NM_133433.4:c.7012G>CMANE SELECT
NP_056199.2:p.Ala2338Pro
NP_597677.2:p.Ala2338Pro
NC_000005.9:g.37051938G>C
NG_006987.1:g.179954G>C
NM_133433.3:c.7012G>C

Protein change:

A2338P

Links:

dbSNP: rs587784030

NCBI 1000 Genomes Browser:

rs587784030

Molecular consequence:

NM_015384.5:c.7012G>C - missense variant - [Sequence Ontology: SO:0001583]
NM_133433.4:c.7012G>C - missense variant - [Sequence Ontology: SO:0001583]

Condition(s)

Name:: Cornelia de Lange syndrome 1 (CDLS1)
Synonyms:: Typus degenerativus amstelodamensis; Brachmann de Lange syndrome
Identifiers:: MONDO: MONDO:0007387; MedGen: C4551851; Orphanet: 199; OMIM: 122470

Recent activity

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Homo sapiens charged multivesicular body protein 4B (CHMP4B), mRNA
Homo sapiens charged multivesicular body protein 4B (CHMP4B), mRNA
gi|260898772|ref|NM_176812.4|

Nucleotide

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV000194027	Genetic Services Laboratory, University of Chicago	criteria provided, single submitter (ACMG Guidelines, 2007)	Likely pathogenic (Feb 20, 2014)	germline	clinical testing	PubMed (1) [See all records that cite this PMID]
SCV001407921	Labcorp Genetics (formerly Invitae), Labcorp	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Pathogenic (Jan 7, 2024)	germline	clinical testing	PubMed (2) [See all records that cite these PMIDs] 26701315, 28492532
SCV002054206	Genome-Nilou Lab	criteria provided, single submitter (ACMG Guidelines, 2015)	Likely pathogenic (Jul 15, 2021)	germline	clinical testing	PubMed (1) [See all records that cite this PMID]

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV000194027

Genetic Services Laboratory, University of Chicago

criteria provided, single submitter

(ACMG Guidelines, 2007)

Likely pathogenic
(Feb 20, 2014)

germline

clinical testing

PubMed (1)
[See all records that cite this PMID]

SCV001407921

Labcorp Genetics (formerly Invitae), Labcorp

criteria provided, single submitter

(Invitae Variant Classification Sherloc (09022015))

Pathogenic
(Jan 7, 2024)

germline

clinical testing

PubMed (2)
[See all records that cite these PMIDs]

SCV002054206

Genome-Nilou Lab

criteria provided, single submitter

(ACMG Guidelines, 2015)

Likely pathogenic
(Jul 15, 2021)

germline

clinical testing

PubMed (1)
[See all records that cite this PMID]

Help

Summary from all submissions

Ethnicity	Origin	Affected	Individuals	Families	Chromosomes tested	Number Tested	Family history	Method
not provided	germline	yes	not provided	not provided	not provided	not provided	not provided	clinical testing
not provided	germline	no	not provided	not provided	not provided	not provided	not provided	clinical testing
not provided	germline	unknown	not provided	not provided	not provided	not provided	not provided	clinical testing

Citations

PubMed

ACMG recommendations for standards for interpretation and reporting of sequence variations: Revisions 2007.

Richards CS, Bale S, Bellissimo DB, Das S, Grody WW, Hegde MR, Lyon E, Ward BE; Molecular Subcommittee of the ACMG Laboratory Quality Assurance Committee..

Genet Med. 2008 Apr;10(4):294-300. doi: 10.1097/GIM.0b013e31816b5cae.

PubMed [citation]

PMID:: 18414213

A series of 38 novel germline and somatic mutations of NIPBL in Cornelia de Lange syndrome.

Nizon M, Henry M, Michot C, Baumann C, Bazin A, Bessières B, Blesson S, Cordier-Alex MP, David A, Delahaye-Duriez A, Delezoïde AL, Dieux-Coeslier A, Doco-Fenzy M, Faivre L, Goldenberg A, Layet V, Loget P, Marlin S, Martinovic J, Odent S, Pasquier L, Plessis G, et al.

Clin Genet. 2016 May;89(5):584-9. doi: 10.1111/cge.12720. Epub 2016 Feb 3.

PubMed [citation]

PMID:: 26701315

See all PubMed Citations (4)

Details of each submission

From Genetic Services Laboratory, University of Chicago, SCV000194027.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (1)

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	yes	not provided	not provided	not provided		not provided	not provided	not provided	not provided

From Labcorp Genetics (formerly Invitae), Labcorp, SCV001407921.3

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (2)

Description

This sequence change replaces alanine, which is neutral and non-polar, with proline, which is neutral and non-polar, at codon 2338 of the NIPBL protein (p.Ala2338Pro). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with Cornelia de Lange syndrome (PMID: 26701315; Invitae). In at least one individual the variant was observed to be de novo. ClinVar contains an entry for this variant (Variation ID: 159217). 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 with a positive predictive value of 80%. For these reasons, this variant has been classified as Pathogenic.

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	unknown	not provided	not provided	not provided		not provided	not provided	not provided	not provided

From Genome-Nilou Lab, SCV002054206.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (1)

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	no	not provided	not provided	not provided		not provided	not provided	not provided	not provided

Last Updated: Sep 29, 2024

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