Congenital hyperinsulinaemic hypoglycaemia (HH) is a rare disorder where episodes of hypoglycaemia are caused by unregulated insulin secretion. Variants in UCP2 (NM_003355. 2) have been reported to cause HH (González-Barroso, et al., 2008) however, since this publication large scale population data have become available which provide important information on the prevalence of rare variants within the population. One such resource is the Genome Aggregation Database (gnomAD)(Lek, et al., 2016) which provides sequencing data from 138,632 individuals. Datasets such as this have revolutionised our ability to interpret variants, as rarity is an important criterion for pathogenicity–the frequency of a variant in a population not selected for the condition should not exceed the prevalence of the condition.

Three studies have reported UCP2 variants in 9 HH patients (table 1). The original paper (González-Barroso, et al., 2008) describes variants in two probands, Snider et al. identified variants in 2 patients out of 417 HH patients screened (Snider, et al., 2013), and Ferrara et al. presented 5 patients with UCP2 variants in a cohort of 211 patients with HH (Ferrara, et al., 2016). Whilst functional studies on the c. 803C> G/p. Ala268Gly variant demonstrated a reduction in UCP2 protein activity (Vozza, et al., 2014), these findings alone are insufficient to assert a causal role of the variant in the aetiology of this disease.