ClinGen Dosage Sensitivity Curation Page


  • Curation Status: Complete

Location Information

Select assembly: (NC_000014.8) (NC_000014.9)
  • Haploinsufficiency score: 3
  • Strength of Evidence (disclaimer): Sufficient evidence for dosage pathogenicity
  • Haploinsufficiency Phenotype: PHEOCHROMOCYTOMA
Evidence for haploinsufficiency phenotype
PubMed ID Description
21685915 Comeno-Mendez et al., (2011) studied 62 cases with pheochromocytoma (PCC) and found 8 pathogenic variants in MAX. They found 3 mutations from 3 independent familial cases with altered initiation codon (c.1A>G), introduced stop codon (c.223C>T) and one causing exon 4 skipping (c.295_1G>A). Immunohistochemical (IHC) analysis showed lack of full length MAX protein. SNP array and multiplex PCR microsatellite confirmed Uniparental disomy (UPD). only silenced paternal allele was found in 2 cases without familial antecedents, suggesting loss of maternal allele accounted for the LOH in all 3 cases. In a cohort of 59 cases, 2 additional truncating mutations affecting exon 3 (c.97C>T) and 4 (c.185_186delA)were identified and confirmed by IHC analysis. Chr.14q LOH was caused by either chromosomal loss or UPD with paternal transmission. PCC was absent in 2 cases who inherited the mutation from their mother and in 2 obligate carriers of a different family.
22452945 Burnichon et al., (2012) found 16 pathogenic variants in MAX affecting 23 subjects with pheochromocytoma. 18 novel variants and 2 previously reported truncating mutations (c.97C>T and c.223C>T) were identified. Mutations affecting initial methionine (c.2T>A), causing a stop codon (c.25del, c.97C>T, c.223C>T and c.244C>T) and 2 deletions, one causing in-frame loss of six highly conserved amino acids (c.140_157del) and one spanning the whole gene (C.1-?_483+?del) were also identified. Paternal mode of transmission was also confirmed.
33815275 Duarte et al., (2021) studied a family of 4 with 3 children having the same deleterious variant (c.97C>T) in MAX as that of their father.
28384794 Bausch et al., (2017) found 8 unrelated individuals with pathogenic variants (c.73C>T, c.146C>G, c.223C>T in 3 cases, c.242-243del, c.292dup and c.307G>T) in MAX.

Haploinsufficiency phenotype comments:

Paternally inherited LOF variants convey an increased risk to Pheochromocytooma/Paraganglioma.

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

Triplosensitivity phenotype comment:

No evidence of triplosensitivity