ATP7A was first reported in relation to X-linked Menkes disease in 1994 (PMID: 7842019). The ATP7A gene encodes a transmembrane protein involved in intracellular copper ion homeostasis. Menkes disease is characterized by short stature, microcephaly, osteoporosis, characteristic hair texture and color, skin laxity, hypotonia, intellectual disability, and seizures.
Sixteen unique variants (missense, nonsense, frameshift, splice) that have been reported in 16 probands in 4 publications (PMIDs: 7977350, 8981948, 21738351, 25771438) are included in this curation. More evidence is available in the literature, but the maximum score for genetic evidence (12 points) has been reached. The mechanism of pathogenicity is loss of function. Accordingly, ATP7A is highly constrained for loss-of-function variants (gnomAD v2.1.1). This gene-disease relationship is also supported by experimental evidence, including functional alteration in patient cells and a mouse model (PMIDs: 16488577, 17483305).
In summary, there is definitive evidence supporting the relationship between ATP7A and X-linked Menkes disease. This classification was originally approved by the ClinGen Intellectual Disability and Autism Gene Curation Expert Panel on February 7, 2018 (SOP Version 5). As of June 2022, this record underwent administrative updates to include an evidence summary text and update scoring to be consistent with SOP Version 9. No new evidence has been added.
ATP7A was first reported in relation to X-linked Menkes disease in 1994 (Kaler et al., PMID: 7842019). The ATP7A gene encodes a transmembrane protein involved in intracellular copper ion homeostasis. Menkes disease is characterized by short stature, microcephaly, osteoporosis, characteristic hair texture and color, skin laxity, hypotonia, intellectual disability, and seizures.
Sixteen variants (missense, nonsense, frameshift, splice) that have been reported in 16 probands in 4 publications (PMIDs: 7977350, 8981948, 21738351, 25771438) are included in this curation. More evidence is available in the literature, but the maximum score for genetic evidence (12 points) has been reached. ATP7A is highly constrained for loss-of-function variants (gnomAD v2.1.1). The mechanism of pathogenicity is loss of function. This gene-disease relationship is also supported by experimental evidence, including functional alteration in patient cells and a mouse model (PMIDs: 16488577, 17483305).
In summary, there is definitive evidence supporting the relationship between ATP7A and X-linked Menkes disease. This has been repeatedly demonstrated in both the research and clinical diagnostic settings, and has been upheld over time. This classification was approved by the ClinGen Intellectual Disability and Autism Gene Curation Expert Panel on February 7, 2018 (SOP Version 5). As of June 2022, this record underwent administrative updates to include an evidence summary text and update scoring to be consistent with SOP Version 9. No new evidence has been added.
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