ClinVar Miner

Submissions for variant NM_000076.2(CDKN1C):c.353C>T (p.Pro118Leu) (rs771731330)

Minimum review status: Collection method:
Minimum conflict level:
ClinVar version:
Total submissions: 2
Download table as spreadsheet
Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Invitae RCV000464222 SCV000541745 uncertain significance Beckwith-Wiedemann syndrome 2018-06-06 criteria provided, single submitter clinical testing This sequence change replaces proline with leucine at codon 118 of the CDKN1C protein (p.Pro118Leu). The proline residue is weakly conserved and there is a moderate physicochemical difference between proline and leucine. While this variant is present in population databases (rs771731330), the frequency information is unreliable, as metrics indicate poor data quality at this position in the ExAC database. This variant has not been reported in the literature in individuals with CDKN1C-related disease. ClinVar contains an entry for this variant (Variation ID: 404254). Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be tolerated, but these predictions have not been confirmed by published functional studies. 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.
University of Washington Department of Laboratory Medicine,University of Washington RCV000664304 SCV000788233 benign Intrauterine growth retardation, metaphyseal dysplasia, adrenal hypoplasia congenita, and genital anomalies; Beckwith-Wiedemann syndrome due to CDKN1C mutation 2018-04-01 criteria provided, single submitter research The CDKN1C variant designated as NM_000076.2:c.353C>T (p.Pro118Leu) is classified as likely benign. The CDKN1C gene is a paternally imprinted gene. Maternally inherited pathogenic variants in the CDKN1C gene are associated with Beckwith-Wiedemann syndrome and IMAGE syndrome. However, missense variants associated with these syndromes are in different domains than the CDKN1C p.Pro118Leu missense variant (Arboleda et al 2012, PMID:22634751), indicating that this variant is less likely to cause disease. Additionally, the variant was maternally inherited in one observed patient who reported no clinical symptoms of Beckwith-Wiedemann syndrome or IMAGE syndrome after four decades of life. Bayesian analysis integrating this data (Tavtigian et al, 2018, PMID:29300386) gives less than 0.1% probability of pathogenicity, which is consistent with a classification of benign. This analysis was performed in conjunction with the family studies project as part of the University of Washington Find My Variant Study.

The information on this website is not intended for direct diagnostic use or medical decision-making without review by a genetics professional. Individuals should not change their health behavior solely on the basis of information contained on this website. Neither the University of Utah nor the National Institutes of Health independently verfies the submitted information. If you have questions about the information contained on this website, please see a health care professional.