The CA5A gene has been associated with autosomal recessive hyperammonemia due to carbonic anhydrase VA deficiency using the ClinGen Clinical Validity Framework. CA5A was first associated with this disease in humans in 2014 (Karnebeek et al, PMID 24530203), and the association has been reported in 13 probands in 2 publications (Karnebeek et al, 2014, PMID 24530203; Diez-Fernandez et al, 2016, PMID 26913920). Six variants (including two missense, one nonsense, one splice site, one intronic deletion, and a single exon deletion) have been described in humans. Of note, deletion of exon 6 has been reported in six probands, all of whom are from the Indian subcontinent. The maximum score for genetic evidence (12 pts.) has been reached. The mechanism for disease is biallelic loss of function. This gene-disease association is supported by the biochemical function of the gene product (carbonic anhydrase VA), and a mouse model (Shah et al, 2013, PMID 23589845). In summary, CA5A is definitively associated with autosomal recessive hyperammonemia due to carbonic anhydrase VA deficiency. This classification was approved by the ClinGen Aminoacidopathies Expert Panel of the Inborn Errors of Metabolic Working Group on September 10th, 2018.
The GenCC data are available free of restriction under a CC0 1.0 Universal (CC0 1.0) Public Domain Dedication. The GenCC requests that you give attribution to GenCC and the contributing sources whenever possible and appropriate. The accepted Flagship manuscript is now available from Genetics in Medicine (https://www.gimjournal.org/article/S1098-3600(22)00746-8/fulltext).
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