SUN-156 Overreporting of Pathogenic Variants in Idiopathic Hypogonadotropic Hypogonadism and Kallmann Syndrome

Abstract Disclosure: L. Grater: None. Z. Hawkins: None. L.C. Layman: None. Introduction: Idiopathic hypogonadotropic hypogonadism (IHH) is a disorder characterized by a deficiency in gonadotropin-releasing hormone (GnRH) neuron migration, or GnRH production or action, leading to delayed or absent sexual development and subsequent infertility. Subtypes of IHH include hyposmic/anosmic (Kallmann syndrome), and normosmic forms. To date, variants in more than 50 genes have been reported as causal in IHH/KS, but not all variants have been confirmed to impair function, potentially overestimating pathogenic variants. We hypothesized that true causative variants as classified by the American College of Medical Genetics and Genomics (ACMG) published guidelines are less common than what are reported. Methods: We reviewed 49 publications reporting 306 IHH/KS-related genetic variants which were considered causal. Each specific variant was entered into VarSome and ClinVar, two search engines that apply the most current ACMG classification: Pathogenic (P), Likely Pathogenic (LP), Variants of Uncertain Significance (VUS), Likely Benign (LB), or Benign (B). Results: 306 variants from 49 studies were described as loss of function, pathogenic, likely pathogenic, disease-causing, deleterious, or damaging, with all terms collectively regarded as indicating pathogenicity. However, using VarSome, 146/306 (47.7%) of purported “causative” variants were classified as either P or LP—78 (25.5%) was deemed as P and 68 (22.2%) as LP. Additionally, 83/306 (27.10%) were classified as VUS and 77/306 (25.2%) were classified as LB or B. ClinVar reported 87/306 (28.4%) as P/LP, 41/306 (13.4%) as VUS, 19/306 (6.2%) as LB/B, 38/306 (12.4%) as “conflicting,” and 121/360 (39.5%) as “no data.” Among the 146 variants classified as LP/P by VarSome, 13.7% were frameshift, 66.4% missense, 17.1% nonsense, and 2.7% noncoding. In contrast, 92.8% of the 83 variants classified as VUS by VarSome were missense, 2.4% nonsense, and 4.8% were in-frame deletions. Conclusions: Just under half of the putative variants were called as P/LP by Varsome, whereas one-fourth were VUS and one-fourth were B/LB. ClinVar only called <30% of these as P/LP. These findings highlight more stringent classification criteria of VarSome and ClinVar, further emphasizing the need for standardized variant classification, based on ACMG guidelines. Supportive evidence for a P/LP variant comes from in silico prediction, low frequency of alleles in the gnomAD database, impaired function in vitro, and segregation with the phenotype in several or numerous families. Failure to meet these benchmarks leads to misclassification, which may affect clinical interpretation and patient care. Presentation: Sunday, July 13, 2025