NM_001122630.2(CDKN1C):c.787G>A (p.Asp263Asn) AND Beckwith-Wiedemann syndrome

Germline classification:: Pathogenic (1 submission)
Last evaluated:: Jun 20, 2022
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:: RCV001380060.8

Allele description [Variation Report for NM_001122630.2(CDKN1C):c.787G>A (p.Asp263Asn)]

NM_001122630.2(CDKN1C):c.787G>A (p.Asp263Asn)

Gene:

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

Variant type:

single nucleotide variant

Cytogenetic location:

11p15.4

Genomic location:

Preferred name:

NM_001122630.2(CDKN1C):c.787G>A (p.Asp263Asn)

HGVS:

NC_000011.10:g.2884670C>T
NG_008022.1:g.6096G>A
NM_000076.2:c.820G>A
NM_001122630.2:c.787G>AMANE SELECT
NM_001122631.2:c.787G>A
NM_001362474.2:c.820G>A
NM_001362475.2:c.255+532G>A
NP_000067.1:p.Asp274Asn
NP_001116102.1:p.Asp263Asn
NP_001116103.1:p.Asp263Asn
NP_001349403.1:p.Asp274Asn
LRG_533t1:c.820G>A
LRG_533:g.6096G>A
LRG_533p1:p.Asp274Asn
NC_000011.9:g.2905900C>T

Protein change:

D263N; ASP274ASN

Links:

OMIM: 600856.0010; dbSNP: rs387907225

NCBI 1000 Genomes Browser:

rs387907225

Molecular consequence:

NM_001362475.2:c.255+532G>A - intron variant - [Sequence Ontology: SO:0001627]
NM_000076.2:c.820G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001122630.2:c.787G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001122631.2:c.787G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001362474.2:c.820G>A - missense variant - [Sequence Ontology: SO:0001583]

Condition(s)

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

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV001577995	Labcorp Genetics (formerly Invitae), Labcorp	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Pathogenic (Jun 20, 2022)	germline	clinical testing	PubMed (6) [See all records that cite these PMIDs] 17576681, 9536098, 24098681, 22634751, 24313804, 28492532

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV001577995

Labcorp Genetics (formerly Invitae), Labcorp

criteria provided, single submitter

(Invitae Variant Classification Sherloc (09022015))

Pathogenic
(Jun 20, 2022)

germline

clinical testing

PubMed (6)
[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

Aberrant 5' splice sites in human disease genes: mutation pattern, nucleotide structure and comparison of computational tools that predict their utilization.

Buratti E, Chivers M, Královicová J, Romano M, Baralle M, Krainer AR, Vorechovsky I.

Nucleic Acids Res. 2007;35(13):4250-63. Epub 2007 Jun 18.

PubMed [citation]

PMID:: 17576681
PMCID:: PMC1934990

Statistical features of human exons and their flanking regions.

Zhang MQ.

Hum Mol Genet. 1998 May;7(5):919-32.

PubMed [citation]

PMID:: 9536098

See all PubMed Citations (6)

Details of each submission

From Labcorp Genetics (formerly Invitae), Labcorp, SCV001577995.5

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (6)

Description

This sequence change replaces aspartic acid, which is acidic and polar, with asparagine, which is neutral and polar, at codon 274 of the CDKN1C protein (p.Asp274Asn). This variant also falls at the last nucleotide of exon 1, which is part of the consensus splice site for this exon. For these reasons, this variant has been classified as Pathogenic. Variants that disrupt the consensus splice site are a relatively common cause of aberrant splicing (PMID: 17576681, 9536098). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. Experimental studies have shown that this missense change affects CDKN1C function (PMID: 24098681). Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Not Available"; Align-GVGD: "Class C0"). ClinVar contains an entry for this variant (Variation ID: 35531). This missense change has been observed in individual(s) with IMAGe syndrome (PMID: 22634751, 24313804). In at least one individual the variant was observed to be de novo. This variant is not present in population databases (gnomAD no frequency).

#	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 25, 2025

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