ANO6 was first reported in relation to autosomal recessive Scott syndrome in 2010 (Suzuki J, et al., PMID: 21107324). At least 6 unique variants (nonsense, splicing, frameshift, and large deletion) have been reported in humans. Evidence supporting this gene-disease relationship includes case-level data and experimental data. Variants in this gene have been reported in at least 5 probands in 5 publications (PMIDs: 21107324, 21511967, 27879994, 37455884, 38492852). Variants in this gene segregated with disease in 1 additional family member. The mechanism for disease is homozygous loss of function. This gene-disease relationship is supported by the biochemical function of ANO6 as a transmembrane protein essential for the calcium-dependent exposure of phosphatidylserine (PMID: 21107324), defects in which are responsible for a reduced catalytic platelet surface, which leads to reduced thrombin generation and impaired clot formation in patient cells (PMID: 27879994). Both dog and mouse models recapitulate the defect in phosphatidylserine exposure and bleeding abnormalities (PMIDs: 11895776, 23021219). In summary, there is moderate evidence to support this gene-disease relationship. While more evidence is needed to establish this relationship definitively, no convincing contradictory evidence has emerged.
This gene-disease pair was previously evaluated by the HT GCEP on 05/27/2020 and 06/22/2022. It was reevaluated on 05/28/2025 and two new cases were identified (PMIDs: 37455884, 38492852) however the classification did not change.
Of note, an additional patient has been identified but is not yet reported in the literature or ClinVar. The patient has reduced/absent thrombin generation and is compound heterozygous for p.R67X/p.E669Dfs*41.
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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