ClinGen Dosage Sensitivity Curation Page


Curation Status: Complete

Gene Information

Location Information

Evidence for Loss Phenotypes

Evidence for loss of function phenotype
PubMed ID Description
20503313 Romanelli et al (2010) reported 8 sequence variants in CDKN1C - one was a de novo frameshift variant and 4 others were maternally inherited loss-of-function variants in patients with BWS. In addition, this manuscript provides a review of other variants described in previous studies.
23197429 Kantaputra et al (2013) reported a novel variant in CDKN1C (c.579delT; p.A193AfsX46) found in all three affected sibs with BWS and their mother. This variant was not detected in 100 normal controls and in more than 12,000 exomes at the Exome Variant Server (
26077438 Brioude et at (2015) identified 37 heterozygous variants in CDKN1C 38 families (50 patients and 7 fetuses). The spectrum of the variants: 4 missense, 9 nonsense, 2 out of frame , 20 frameshift , and 2 splice site. Five out of these 37 variants (c.125T>C, c.176C>T, c.688C>T,c.812C>A, and c.812C>G) were recurrent variants, which have already been reported in BWS patients. Therefore, the authors identified 32 novel CDKN1C variants. Analysis of parental samples when available showed that all variants tested but one was inherited from the mother.

Evidence for Triplosenstive Phenotype

Evidence for triplosensitivity phenotype
PubMed ID Description
26358311 Xue et al (2015) described a paternal duplication of the 11p15 centromeric imprinting control region which was associated with increased expression of CDKN1C in a child with Silver?Russell syndrome (SRS). The microduplication was discontiguous, with a 34 kb and a 237 kb duplications separated by a 3.3 kb region with normal copy number. Genes located within the duplication include portions of KCNQ1 and KCNQ1OT1 and the entire CDKN1C, SLC22A18, SLC22A18AS, and PHLDA2. Normally paternally inherited CDKN1C is not expressed but the microduplication of paternal origin in this patient appeared to lead to increased expression of CDKN1C. The authors suggested that the expression of CDKN1C in the patient was not regulated by the methylation of IC2. A plausible explanation was that the duplication resulted in an aberrant KCNQ1OT1 transcript that was unstable.

NOTE:The loss of function score should be used to evaluate deletions, and the triplosensitivity score should be used to evaluated duplications. CNVs encompassing more than one gene must be evaluated in their totality (e.g. overall size, gain vs. loss, presence of other genes, etc). The rating of a single gene within the CNV should not necessarily be the only criteria by which one defines a clinical interpretation. Individual interpretations must take into account the phenotype described for the patient as well as issues of penetrance and expressivity of the disorder. ACMG has published guidelines for the characterization of postnatal CNVs, and these recommendations should be utilized (Genet Med (2011)13: 680-685). Exceptions to these interpretive correlations will occur, and clinical judgment should always be exercised.