ClinGen Dosage Sensitivity Curation Page

ATP7A

  • Curation Status: Complete

Location Information

Select assembly: (NC_000023.10) (NC_000023.11)
  • Haploinsufficiency score: 3
  • Strength of Evidence (disclaimer): Sufficient evidence for dosage pathogenicity
  • Haploinsufficiency Phenotype: MENKES DISEASE
Evidence for haploinsufficiency phenotype
PubMed ID Description
14635105 Tumer et al., 2013 performed review of 274 previously published and 18 novel variants in ATP7A associated with Menkes disease or occipital horn syndrome. All variants except 89 missense variants and a single dinucleotide inversion were predicted to result in nonfunctional truncated protein or nonsense mediated decay, suggesting loss of function mechanism for these diseases. Seven chromosome abnormalities were reported, including a male with an insertional event, inherited from a mother with preferential inactivation of the affected chromosome. The remaining females with chromosome abnormalities included a female patient with mosaic Turner syndrome, and five females with X;autosome translocations in which the derivative X chromosome was preferentially active, leading to a Menkes disease phenotype.
32994893 Mhaske 2020 compiled reported variants in ATP7A into a comprehensive database that included 602 variants. The authors concluded that nonsense, frameshift-insertion, and deletions which are truncating and cause protein disruption typically lead to severe phenotypes.

Haploinsufficiency phenotype comments:

Loss of function variants in ATP7A cause ATP7A-related copper transport disorders (Menkes syndrome and occipital horn syndrome in males). Female carriers are typically asymptomatic. 15% of variants identified are partial or whole gene deletions. ATP7A-related distal motor neuropathy is caused by unique missense variants rather than loss of function variants. See GeneReviews for additional information (https://www.ncbi.nlm.nih.gov/books/NBK1413/).

The loss-of-function and triplosensitivity ratings for genes on the X chromosome are made in the context of a male genome to account for the effects of hemizygous duplications or nullizygous deletions. In contrast, disruption of some genes on the X chromosome causes male lethality and the ratings of dosage sensitivity instead take into account the phenotype in female individuals. Factors that may affect the severity of phenotypes associated with X-linked disorders include the presence of variable copies of the X chromosome (i.e. 47,XXY or 45,X) and skewed X-inactivation in females.

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

The loss-of-function and triplosensitivity ratings for genes on the X chromosome are made in the context of a male genome to account for the effects of hemizygous duplications or nullizygous deletions. In contrast, disruption of some genes on the X chromosome causes male lethality and the ratings of dosage sensitivity instead take into account the phenotype in female individuals. Factors that may affect the severity of phenotypes associated with X-linked disorders include the presence of variable copies of the X chromosome (i.e. 47,XXY or 45,X) and skewed X-inactivation in females.