Overestimation of Pathogenic Variants in Idiopathic Hypogonadotropic Hypogonadism and Kallmann Syndrome

Objectives: Idiopathic hypogonadotropic hypogonadism and Kallmann syndrome are rare disorders of deficient gonadotropin-releasing hormone migration, secretion, and/or action causing delayed or absent puberty and infertility. Variants in >50 genes have been reported as causative, but many lack functional validation, potentially overestimating pathogenicity. We hypothesized that the number of true causative variants, when classified by the American College of Medical Genetics and Genomics (ACMG) guidelines, is fewer than reported. Methods: We reviewed literature for variants in the 27 Online Mendelian Inheritance in Man-established causative genes for idiopathic hypogonadotropic hypogonadism/Kallmann syndrome. Variants were identified through database and literature searches. Publications were screened for variants explicitly reported by authors as causative or equivalent terminology. The reported variants were reclassified using VarSome and ClinVar applying 2015 ACMG criteria. Publications were categorized as preguidelines (≤2015) or postguidelines (>2015) for comparative analysis. Results: Two hundred seventy-three publications met inclusion, yielding 933 variants. VarSome classified 444/933 (47.6%) as pathogenic/likely pathogenic (P/LP), 249 (26.7%) as variants of uncertain significance (VUS), and 240 (25.7%) as benign/likely benign (B/LB). ClinVar classified 171/933 (18.3%) as P/LP, 104 (11.1%) as VUS, 68 (7.3%) as B/LB, 85 (9.1%) as conflicting, 13 (1.4%) as risk factor, and 492 (52.7%) as lacking entries. In VarSome, 37.2% of P/LP and 84.3% of VUS were missense. Conclusions: Just under half of the reported variants were reclassified as P/LP by VarSome, whereas one-fourth were VUS and one-fourth B/LB. ClinVar called <20% of these P/LP. These findings highlight overestimation of pathogenicity and the need for standardized variant interpretation using supportive evidence consistent with ACMG guidelines.