NM_133433.4(NIPBL):c.2584A>G (p.Lys862Glu) AND Cornelia de Lange syndrome 1

Germline classification:: Uncertain significance (2 submissions)
Last evaluated:: Jul 15, 2021
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:: RCV000678375.4

Allele description [Variation Report for NM_133433.4(NIPBL):c.2584A>G (p.Lys862Glu)]

NM_133433.4(NIPBL):c.2584A>G (p.Lys862Glu)

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.2584A>G (p.Lys862Glu)

HGVS:

NC_000005.10:g.36985764A>G
NG_006987.1:g.113882A>G
NG_006987.2:g.113882A>G
NM_015384.5:c.2584A>G
NM_133433.4:c.2584A>GMANE SELECT
NP_056199.2:p.Lys862Glu
NP_597677.2:p.Lys862Glu
NC_000005.9:g.36985866A>G
NM_133433.3:c.2584A>G

Protein change:

K862E

Links:

dbSNP: rs1554017428

NCBI 1000 Genomes Browser:

rs1554017428

Molecular consequence:

NM_015384.5:c.2584A>G - missense variant - [Sequence Ontology: SO:0001583]
NM_133433.4:c.2584A>G - missense variant - [Sequence Ontology: SO:0001583]

Observations:

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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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV000804442	Geisinger Autism and Developmental Medicine Institute, Geisinger Health System	criteria provided, single submitter (ACMG Guidelines, 2015)	Uncertain significance (Aug 28, 2017)	unknown	provider interpretation, clinical testing	PubMed (3) [See all records that cite these PMIDs] 15146186, 15146185, 25741868
SCV002055947	Genome-Nilou Lab	criteria provided, single submitter (ACMG Guidelines, 2015)	Uncertain significance (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

SCV000804442

Geisinger Autism and Developmental Medicine Institute, Geisinger Health System

criteria provided, single submitter

(ACMG Guidelines, 2015)

Uncertain significance
(Aug 28, 2017)

unknown

provider interpretation, clinical testing

PubMed (3)
[See all records that cite these PMIDs]

SCV002055947

Genome-Nilou Lab

criteria provided, single submitter

(ACMG Guidelines, 2015)

Uncertain significance
(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	unknown	unknown	1	not provided	not provided	1	not provided	clinical testing, provider interpretation
not provided	germline	no	not provided	not provided	not provided	not provided	not provided	clinical testing

Citations

PubMed

Cornelia de Lange syndrome is caused by mutations in NIPBL, the human homolog of Drosophila melanogaster Nipped-B.

Krantz ID, McCallum J, DeScipio C, Kaur M, Gillis LA, Yaeger D, Jukofsky L, Wasserman N, Bottani A, Morris CA, Nowaczyk MJ, Toriello H, Bamshad MJ, Carey JC, Rappaport E, Kawauchi S, Lander AD, Calof AL, Li HH, Devoto M, Jackson LG.

Nat Genet. 2004 Jun;36(6):631-5. Epub 2004 May 16.

PubMed [citation]

PMID:: 15146186
PMCID:: PMC4902017

NIPBL, encoding a homolog of fungal Scc2-type sister chromatid cohesion proteins and fly Nipped-B, is mutated in Cornelia de Lange syndrome.

Tonkin ET, Wang TJ, Lisgo S, Bamshad MJ, Strachan T.

Nat Genet. 2004 Jun;36(6):636-41. Epub 2004 May 16.

PubMed [citation]

PMID:: 15146185

See all PubMed Citations (3)

Details of each submission

From Geisinger Autism and Developmental Medicine Institute, Geisinger Health System, SCV000804442.2

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	provider interpretation	PubMed (3)
2	not provided	1	not provided	not provided	clinical testing	PubMed (3)

Description

This 5 year old male with global developmental delays, seizure disorder, and subcortical band heterotopia was found to carry a variant in the NIPBL gene. Inheritance is unknown as a paternal sample was unavailable. Clinical correlation is thought to be poor as the patient is non-dysmorphic and does not have limb defects. He is small for his age; he is below the 1st percentile for both height and weight. The variant is absent from population databases. It is a non-conservative substitution at a conserved position; in silico analysis is inconsistent in its predictions. Additionally, exome sequencing identified a pathogenic variant in PAFAH1B1.

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

From Genome-Nilou Lab, SCV002055947.1

#	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: Dec 11, 2022

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