ClinGen Dosage Sensitivity Curation Page


  • Curation Status: Complete

Location Information

Select assembly: (NC_000012.11) (NC_000012.12)
Evidence for haploinsufficiency 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).

Haploinsufficiency phenotype comments:

Loss of function variants are consistent with multiple endocrine neoplasia, type IV (MEN4) syndrome. Additional evidence: Pellegata et al. (2006) (PMID 17030811) describe a germline nonsense variant (c.G692A, p.W76X) in a 48-year-old female with acromegaly and history of invasive pituitary adenoma and primary hyperparathyroidism. Previous sequencing of MEN1 was negative. Additional family studies revealed one genotype+ sibling with history of renal angiomyolipoma, described by the authors as "an MEN1-associated nonendocrine tumor." The proband has a younger, 44-year-old genotype+ sibling; this sibling has a genotype+ child (teenager). These individuals report no symptoms, though the author notes that they "did not undergo thorough medical examination." The proband's mother was genotype-; her father, deceased, was said to have acromegaly. The authors were able to infer from haplotype analysis that the variant was inherited from the proband's father. In this publication, the authors also discuss the analogous (though autosomal recessive) MENX syndrome in rats; study of this phenotype led them to sequence the CDKN1B gene in the aforementioned proband. The authors report fine mapping of the Menx locus and the eventual discovery of a homozygous frameshift variant in rat Cdnk1b; they also show that these rats have a "dramatic" reduction in the resulting protein. Cellular localization studies of the human variant (W76X) in human MCF-7 and embryonic kidney (HEK) 293T cell lines show that the human variant prevents truncated p27 protein from entering the nucleus. Tonelli et al. (2014) (PMID 24819502): A frameshift variant (c.371delCT at codon 125 in exon 1) was identified in a female in her 50s with a history of persistent/recurrent primary hyperparathyroidism and neuroendocrine tumors of the gastro-entero-pancreatic tract. Sequencing of the MEN1 gene was negative. The variant was also identified in her son, who was reportedly asymptomatic (with the exception of "calcemia in the upper normal range") in his mid-30s. No other at-risk relatives agreed to testing. Additionally, at least two variants have been reported in the 5'UTR of this gene: Occhi et al. (2013) (PMID: 23555276): The authors "identified a 4-bp deletion [c.-456_-453delCCTT, NM_004064] that modifies the regulatory uORF [upstream open reading frame] in the 5?UTR of the CDKN1B gene in a [62-year-old female] patient with tumors in the pituitary gland and the endocrine pancreas. Functional studies based on dual-luciferase assay and site-directed mutagenesis further support the deleterious influence of this deletion on translation reinitiation at the CDKN1B starting site, with a consequent reduction of p27KIP1 expression both in vitro and in vivo." Malanga et al. (2012) (PMID:22129891): The authors "report the identification of a heterozygous GAGA deletion in the 5'-UTR of CDKN1B, NM_004064.3:c.-32_-29del, in a [69-year-old female] patient affected by gastric carcinoid tumor and hyperparathyroidism [family history is reportedly negative]. This deletion falls inside the region that is responsible for CDKN1B transcription and is predicted to destroy a secondary stem and loop structure that includes the GAGAGA element responsible for ribosome recruitment. Accordingly, in vitro studies of coupled transcription/translation assays and transient transfection in HeLa cells showed that the GAGA deletion in the CDKN1B 5'-UTR significantly impairs the transcription of downstream reporter luciferase (of ?40-60%) and, possibly, the translation of the corresponding mRNA. This mutation was associated with a significant reduction in the amount of CDKN1B mRNA in peripheral blood leukocytes from the patient, as demonstrated by quantitative real-time PCR." Of note, there are also several additional putative loss of function variants reported as either likely pathogenic or pathogenic by clinical laboratory submitters who have provided assertion criteria (i.e., "one star submitters"). These variants have not been described in the literature, and no information is available about the probands in whom they were observed.

  • Triplosensitivity score: 0
  • Strength of Evidence (disclaimer): No evidence for dosage pathogenicity

Triplosensitivity phenotype comment:

no evidence for triplosensitivity