NM_133433.4(NIPBL):c.6860T>C (p.Leu2287Pro) AND Cornelia de Lange syndrome 1

Germline classification:: Likely pathogenic (1 submission)
Last evaluated:: Dec 27, 2023
Review status:: 1 star out of maximum of 4 stars
criteria provided, single submitter

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:: RCV003498863.2

Allele description [Variation Report for NM_133433.4(NIPBL):c.6860T>C (p.Leu2287Pro)]

NM_133433.4(NIPBL):c.6860T>C (p.Leu2287Pro)

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.6860T>C (p.Leu2287Pro)

HGVS:

NC_000005.10:g.37049207T>C
NG_006987.2:g.177325T>C
NM_015384.5:c.6860T>C
NM_133433.4:c.6860T>CMANE SELECT
NP_056199.2:p.Leu2287Pro
NP_597677.2:p.Leu2287Pro
NC_000005.9:g.37049309T>C

Protein change:

L2287P

Molecular consequence:

NM_015384.5:c.6860T>C - missense variant - [Sequence Ontology: SO:0001583]
NM_133433.4:c.6860T>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

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Concise Conserved Domain Links for Protein (Select 306991837) (1)
Conserved Domains
Fibroblast growth factor 2 restimulation effect on embryonic fibroblast
Fibroblast growth factor 2 restimulation effect on embryonic fibroblast
Accession: GDS2422

GEO DataSets
Related DataSets for GEO Profiles (Select 32238776) (1)
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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV004365845	Labcorp Genetics (formerly Invitae), Labcorp	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Likely pathogenic (Dec 27, 2023)	germline	clinical testing	PubMed (2) [See all records that cite these PMIDs] 34717699, 28492532

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV004365845

Labcorp Genetics (formerly Invitae), Labcorp

criteria provided, single submitter

(Invitae Variant Classification Sherloc (09022015))

Likely pathogenic
(Dec 27, 2023)

germline

clinical testing

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

Help

Summary from all submissions

Ethnicity	Origin	Affected	Individuals	Families	Chromosomes tested	Number Tested	Family history	Method
not provided	germline	unknown	not provided	not provided	not provided	not provided	not provided	clinical testing

Citations

PubMed

High rate of autonomic neuropathy in Cornelia de Lange Syndrome.

Pablo MJ, Pamplona P, Haddad M, Benavente I, Latorre-Pellicer A, Arnedo M, Trujillano L, Bueno-Lozano G, Kerr LM, Huisman SA, Kaiser FJ, Ramos F, Kline AD, Pie J, Puisac B.

Orphanet J Rare Dis. 2021 Oct 30;16(1):458. doi: 10.1186/s13023-021-02082-y.

PubMed [citation]

PMID:: 34717699
PMCID:: PMC8556971

Sherloc: a comprehensive refinement of the ACMG-AMP variant classification criteria.

Nykamp K, Anderson M, Powers M, Garcia J, Herrera B, Ho YY, Kobayashi Y, Patil N, Thusberg J, Westbrook M; Invitae Clinical Genomics Group., Topper S.

Genet Med. 2017 Oct;19(10):1105-1117. doi: 10.1038/gim.2017.37. Epub 2017 May 11. Erratum in: Genet Med. 2020 Jan;22(1):240. doi: 10.1038/s41436-019-0624-9.

PubMed [citation]

PMID:: 28492532
PMCID:: PMC5632818

Details of each submission

From Labcorp Genetics (formerly Invitae), Labcorp, SCV004365845.1

#	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 leucine, which is neutral and non-polar, with proline, which is neutral and non-polar, at codon 2287 of the NIPBL protein (p.Leu2287Pro). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with clinical features of Cornelia de Lange syndrome (PMID: 34717699; Invitae). 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 95%. In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely 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

Last Updated: Sep 29, 2024

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