NM_133433.4(NIPBL):c.1436G>A (p.Arg479Gln) AND Cornelia de Lange syndrome 1

Germline classification:: Uncertain significance (2 submissions)
Last evaluated:: Jul 30, 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:: RCV001810312.3

Allele description [Variation Report for NM_133433.4(NIPBL):c.1436G>A (p.Arg479Gln)]

NM_133433.4(NIPBL):c.1436G>A (p.Arg479Gln)

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.1436G>A (p.Arg479Gln)

HGVS:

NC_000005.10:g.36976343G>A
NG_006987.2:g.104461G>A
NM_015384.5:c.1436G>A
NM_133433.4:c.1436G>AMANE SELECT
NP_056199.2:p.Arg479Gln
NP_597677.2:p.Arg479Gln
NC_000005.9:g.36976445G>A
NM_133433.3:c.1436G>A

Protein change:

R479Q

Links:

dbSNP: rs1017711925

NCBI 1000 Genomes Browser:

rs1017711925

Molecular consequence:

NM_015384.5:c.1436G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_133433.4:c.1436G>A - 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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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV002058892	3billion	criteria provided, single submitter (ACMG Guidelines, 2015)	Uncertain significance (Jul 30, 2024)	germline	clinical testing	PubMed (1) [See all records that cite this PMID]
SCV004353738	Invitae	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Uncertain significance (Nov 12, 2023)	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

SCV002058892

3billion

criteria provided, single submitter

(ACMG Guidelines, 2015)

Uncertain significance
(Jul 30, 2024)

germline

clinical testing

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

SCV004353738

Invitae

criteria provided, single submitter

(Invitae Variant Classification Sherloc (09022015))

Uncertain significance
(Nov 12, 2023)

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	unknown	not provided	not provided	not provided	not provided	not provided	clinical testing

Citations

PubMed

Standards and guidelines for the interpretation of sequence variants: a joint consensus recommendation of the American College of Medical Genetics and Genomics and the Association for Molecular Pathology.

Richards S, Aziz N, Bale S, Bick D, Das S, Gastier-Foster J, Grody WW, Hegde M, Lyon E, Spector E, Voelkerding K, Rehm HL; ACMG Laboratory Quality Assurance Committee..

Genet Med. 2015 May;17(5):405-24. doi: 10.1038/gim.2015.30. Epub 2015 Mar 5.

PubMed [citation]

PMID:: 25741868
PMCID:: PMC4544753

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 3billion, SCV002058892.2

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

Description

The variant is observed at an extremely low frequency in the gnomAD v4.0.0 dataset (total allele frequency: <0.001%). In silico tool predictions suggest damaging effect of the variant on gene or gene product [3Cnet: 0.92 (>=0.6)]. A different missense change at the same codon (p.Arg479Gly) has been reported to be associated with NIPBL related disorder (ClinVar ID: VCV000915346). Therefore, this variant is classified as uncertain significance according to the recommendation of ACMG/AMP guideline.

#	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 Invitae, SCV004353738.1

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

Description

This sequence change replaces arginine, which is basic and polar, with glutamine, which is neutral and polar, at codon 479 of the NIPBL protein (p.Arg479Gln). This variant is not present in population databases (gnomAD no frequency). This variant has not been reported in the literature in individuals affected with NIPBL-related conditions. ClinVar contains an entry for this variant (Variation ID: 1311194). 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%. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance.

#	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: Aug 11, 2024

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