ClinGen Dosage Sensitivity Curation Page

CDKN1B

Curation Status: Complete

Gene Information

Location Information

Evidence for Loss Phenotypes

Evidence for loss of function phenotype
PubMed ID Description
30990521 Frederiksen et al. (2019) report a frameshift variant (c.121_122delTT, p.Leu41Asnfs*83) in an individual with a history of primary hyperparathyroidism and Cushing disease caused by the presence of a pituitary tumor. The variant was identified after "genetic screening of CaSR, RET, intron-exon junctions, and coding regions as well as large deletions of MEN1 and CDKN1B." Subsequent testing within this individual's family identified 12 additional carriers across 2 generations. Eleven of the 12 additional family members were shown to have "mild, asymptomatic hypercalcemia due to primary hyperparathyroidism" (measurements were not available for the 12th individual). Nonfunctioning pituitary tumors were identified in three of the 12 family members, and the proband's mother was also diagnosed with a metastatic neuroendocrine tumor.
17519308 Georgitsi et al. (2007) report a germline 19bp duplication "in exon1, which changes the amino acid sequence after 26 residues and leads to a premature stop codon 69 amino acids earlier than the wild type." This variant was identified in a Dutch female with clinically suspected MEN1 but negative MEN1 seqencing. She has a history of small-cell neuroendocrine cervical carcinoma, ACTH-secreting pituitary adenoma, and hyperparathyroidism. The authors report negative family history for any MEN-related phenotypes, and parental testing was not performed.
29036195 Pardi et al. (2017): The authors sequenced MEN1, CDKN1B, and AIP in a large Italian cohort of individuals with clinical diagnoses of MEN1 or familial isolated hyperparathyroidism. A frameshift variant in CDKN1B (c.374_375delCT, p.Ser125Ter) was detected in a single individual with a clinical diagnosis of MEN1 (multiglandular primary hyperparathyroidism and multiple gastro-entero-pancreatic tumors). This proband and variant were discussed in Pardi et al. 2015 (PMID: 25416039).

Evidence for Triplosenstive Phenotype

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.