APPL1 was first reported in relation to apparent autosomal dominant diabetes in 2015 (Prudente et al., PMID: 26073777). Evidence supporting this gene-disease relationship includes case level data, segregation data, and experimental data. Summary of genetic and experimental evidence: 7.0 points. Missense, nonsense, and frameshift variants in this gene have been reported in at least 4 probands in 2 publications (PMIDs: 26073777, 31264968); however, two of these probands (PMID 31264968) were selected on the basis of long-surviving type 1 diabetes and had a phenotype consistent with type 1 diabetes (HLA risk alleles and C-peptide- +/- GAD positivity); therefore, they were not counted in the evidence scoring. The other two probands (PMID 26073777) contributed 2 points of variant-level evidence but were selected for diabetes onset before age 35 with a 3 generation family history of diabetes on one side and a first degree relative diagnosed with diabetes before 35, broader than criteria typically used for monogenic diabetes/MODY studies. The p.Leu552* variant in this gene segregated with diabetes or prediabetes in 10 additional family members (PMID:26073777), resulting in a LOD score of 2.71 (1 point). Notably, 7/10 of these individuals were diagnosed at 35 years or older and 9/10 were overweight or obese. Furthermore, there were 5 p.Leu552* carriers 35 years or older with normal glucose tolerance. Thus the variant may be contributory, but penetrance is lower than typical of monogenic diabetes. Summary of case-level and segregation data: 3.0 points. The mechanism for disease is currently unknown, but expression studies, animal models, and cell culture models provide evidence for a role in insulin secretion (PMIDs: 23793716, 26073777). Summary of experimental evidence: 4.0 points. In summary, there is limited evidence to support this gene-disease relationship. While more evidence is needed to establish this relationship, no convincing contradictory evidence has emerged. Although the total score (7.0) is in the moderate range, the lack of genetic evidence outside a single publication and the low penetrance and the broad definition of monogenic diabetes used in that publication led to the EP decision to classify this relationship as limited and requiring further evidence to elevate it.
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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