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NM_133433.4(NIPBL):c.1208C>T (p.Thr403Ile) AND Cornelia de Lange syndrome 1

Germline classification:
Conflicting interpretations of pathogenicity (2 submissions)
Last evaluated:
Jan 11, 2024
Review status:
criteria provided, conflicting classifications
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:
RCV000367940.6

Allele description

NM_133433.4(NIPBL):c.1208C>T (p.Thr403Ile)

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.1208C>T (p.Thr403Ile)
HGVS:
  • NC_000005.10:g.36976115C>T
  • NG_006987.2:g.104233C>T
  • NM_015384.5:c.1208C>T
  • NM_133433.4:c.1208C>TMANE SELECT
  • NP_056199.2:p.Thr403Ile
  • NP_597677.2:p.Thr403Ile
  • NC_000005.9:g.36976217C>T
  • NG_006987.1:g.104233C>T
  • NM_133433.3:c.1208C>T
Protein change:
T403I
Links:
dbSNP: rs746183321
NCBI 1000 Genomes Browser:
rs746183321
Molecular consequence:
  • NM_015384.5:c.1208C>T - missense variant - [Sequence Ontology: SO:0001583]
  • NM_133433.4:c.1208C>T - 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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Assertion and evidence details

Help
Submission AccessionSubmitterReview Status
(Assertion method)		Clinical Significance
(Last evaluated)		OriginMethodCitations
SCV000457268Illumina Laboratory Services, Illumina
criteria provided, single submitter

(ICSL Variant Classification Criteria 13 December 2019)		Likely benign
(Jan 12, 2018) 		germlineclinical testing

Citation Link,

SCV004300598Invitae
criteria provided, single submitter

(Invitae Variant Classification Sherloc (09022015))		Uncertain significance
(Jan 11, 2024) 		germlineclinical testing

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

Help

Summary from all submissions

EthnicityOriginAffectedIndividualsFamiliesChromosomes testedNumber TestedFamily historyMethod
not providedgermlineunknownnot providednot providednot providednot providednot providedclinical testing

Citations

PubMed

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 Illumina Laboratory Services, Illumina, SCV000457268.3

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1not providednot providednot providednot providedclinical testingnot provided

Description

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as likely benign is not then subjected to further curation. The score for this variant resulted in a classification of likely benign for this disease.

#SampleMethodObservation
OriginAffectedNumber testedTissuePurposeMethodIndividualsAllele frequencyFamiliesCo-occurrences
1germlineunknownnot providednot providednot providednot providednot providednot providednot provided

From Invitae, SCV004300598.1

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1not providednot providednot providednot providedclinical testing PubMed (1)

Description

This sequence change replaces threonine, which is neutral and polar, with isoleucine, which is neutral and non-polar, at codon 403 of the NIPBL protein (p.Thr403Ile). This variant is present in population databases (rs746183321, gnomAD 0.02%), including at least one homozygous and/or hemizygous individual. 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: 353372). 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) has been performed at Invitae for this missense variant, however the output from this modeling did not meet the statistical confidence thresholds required to predict the impact of this variant on NIPBL protein function. 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.

#SampleMethodObservation
OriginAffectedNumber testedTissuePurposeMethodIndividualsAllele frequencyFamiliesCo-occurrences
1germlineunknownnot providednot providednot providednot providednot providednot providednot provided

Last Updated: Feb 20, 2024