NM_001122630.2(CDKN1C):c.572dup (p.Ala192fs) AND Beckwith-Wiedemann syndrome

Germline classification:: Pathogenic (1 submission)
Last evaluated:: Jun 6, 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:: RCV003502791.1

Allele description [Variation Report for NM_001122630.2(CDKN1C):c.572dup (p.Ala192fs)]

NM_001122630.2(CDKN1C):c.572dup (p.Ala192fs)

Gene:

CDKN1C:cyclin dependent kinase inhibitor 1C [Gene - OMIM - HGNC]

Variant type:

Duplication

Cytogenetic location:

11p15.4

Genomic location:

Preferred name:

NM_001122630.2(CDKN1C):c.572dup (p.Ala192fs)

HGVS:

NC_000011.10:g.2884888dup
NG_008022.1:g.5881dup
NG_121670.1:g.224dup
NM_000076.2:c.605dup
NM_001122630.2:c.572dupMANE SELECT
NM_001122631.2:c.572dup
NM_001362474.2:c.605dup
NM_001362475.2:c.255+317dup
NP_000067.1:p.Ala203fs
NP_001116102.1:p.Ala192fs
NP_001116103.1:p.Ala192fs
NP_001349403.1:p.Ala203fs
LRG_533t1:c.605dup
LRG_533:g.5881dup
LRG_533p1:p.Ala203fs
NC_000011.9:g.2906114_2906115insG
NC_000011.9:g.2906118dup

Protein change:

A192fs

Molecular consequence:

NM_000076.2:c.605dup - frameshift variant - [Sequence Ontology: SO:0001589]
NM_001122630.2:c.572dup - frameshift variant - [Sequence Ontology: SO:0001589]
NM_001122631.2:c.572dup - frameshift variant - [Sequence Ontology: SO:0001589]
NM_001362474.2:c.605dup - frameshift variant - [Sequence Ontology: SO:0001589]
NM_001362475.2:c.255+317dup - intron variant - [Sequence Ontology: SO:0001627]

Condition(s)

Name:: Beckwith-Wiedemann syndrome (BWS)
Synonyms:: Exomphalos macroglossia gigantism syndrome; EMG Syndrome
Identifiers:: MONDO: MONDO:0007534; MedGen: C0004903; Orphanet: 116; OMIM: 130650

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Satellite Cells, Perineuronal
Satellite Cells, Perineuronal
The non-neuronal cells that surround the neuronal cell bodies of the GANGLIA. They are distinguished from the perineuronal satellite oligodendrocytes (OLIGODENDROGLIA) found i...<br/>Year introduced: 2002

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV004246370	Invitae	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Pathogenic (Jun 6, 2023)	germline	clinical testing	PubMed (2) [See all records that cite these PMIDs] 26077438, 28492532

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV004246370

Invitae

criteria provided, single submitter

(Invitae Variant Classification Sherloc (09022015))

Pathogenic
(Jun 6, 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

Mutations of the Imprinted CDKN1C Gene as a Cause of the Overgrowth Beckwith-Wiedemann Syndrome: Clinical Spectrum and Functional Characterization.

Brioude F, Netchine I, Praz F, Le Jule M, Calmel C, Lacombe D, Edery P, Catala M, Odent S, Isidor B, Lyonnet S, Sigaudy S, Leheup B, Audebert-Bellanger S, Burglen L, Giuliano F, Alessandri JL, Cormier-Daire V, Laffargue F, Blesson S, Coupier I, Lespinasse J, et al.

Hum Mutat. 2015 Sep;36(9):894-902. doi: 10.1002/humu.22824. Epub 2015 Aug 6.

PubMed [citation]

PMID:: 26077438

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 Invitae, SCV004246370.1

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

Description

For these reasons, this variant has been classified as Pathogenic. This variant disrupts a region of the CDKN1C protein in which other variant(s) (p.Pro302Leufs*19) have been determined to be pathogenic (PMID: 26077438; Invitae). This suggests that this is a clinically significant region of the protein, and that variants that disrupt it are likely to be disease-causing. This variant has not been reported in the literature in individuals affected with CDKN1C-related conditions. The frequency data for this variant in the population databases is considered unreliable, as metrics indicate insufficient coverage at this position in the gnomAD database. This sequence change creates a premature translational stop signal (p.Ala203Glyfs*38) in the CDKN1C gene. While this is not anticipated to result in nonsense mediated decay, it is expected to disrupt the last 114 amino acid(s) of the CDKN1C protein.

#	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: Feb 20, 2024

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