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<p>Abstract</p> <p>Background</p> <p>The <it>SH2B1</it> gene (Src-homology 2B adaptor protein 1 gene) is a solid candidate gene for obesity. Large scale GWAS studies depicted markers in the vicinity of the gene; animal models suggest a potential relevance for human body weight regulation.</p> <p>Methods</p> <p>We performed a mutation screen for variants in the <it>SH2B1</it> coding sequence in 95 extremely obese children and adolescents. Detected variants were genotyped in independent childhood and adult study groups (up to 11,406 obese or overweight individuals and 4,568 controls). Functional implications on STAT3 mediated leptin signalling of the detected variants were analyzed <it>in vitro</it>.</p> <p>Results</p> <p>We identified two new rare mutations and five known SNPs (rs147094247, rs7498665, rs60604881, rs62037368 and rs62037369) in <it>SH2B1</it>. Mutation g.9483C/T leads to a non-synonymous, non-conservative exchange in the beta (βThr656Ile) and gamma (γPro674Ser) splice variants of <it>SH2B1</it>. It was additionally detected in two of 11,206 (extremely) obese or overweight children, adolescents and adults, but not in 4,506 population-based normal-weight or lean controls. The non-coding mutation g.10182C/A at the 3’ end of <it>SH2B1</it> was only detected in three obese individuals. For the non-synonymous SNP rs7498665 (Thr484Ala) we observed nominal over-transmission of the previously described risk allele in 705 obesity trios (nominal p = 0.009, OR = 1.23) and an increased frequency of the same allele in 359 cases compared to 429 controls (nominal p = 0.042, OR = 1.23). The obesity risk-alleles at Thr484Ala and <it>β</it>Thr656Ile/<it>γ</it>Pro674Ser had no effect on STAT3 mediated leptin receptor signalling in splice variants <it>β</it> and <it>γ</it>.</p> <p>Conclusion</p> <p>The rare coding mutation <it>β</it>Thr656Ile/<it>γ</it>Pro674Ser (g.9483C/T) in <it>SH2B1</it> was exclusively detected in overweight or obese individuals. Functional analyzes did not reveal impairments in leptin signalling for the mutated SH2B1.</p>