Overestimation of Pathogenic Variants in Idiopathic Hypogonadotropic Hypogonadism and Kallmann Syndrome
Authors' conclusion
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.
Study context
- Population
- Variants reported as causative in the 27 OMIM-established causative genes for idiopathic hypogonadotropic hypogonadism/Kallmann syndrome273 publications
- Participants
- 933 participants
- Comparison
- VarSome vs ClinVar
- Outcome
- Reclassification of reported causative variants
Methodological detailsreclassification by VarSome and ClinVar applying 2015 ACMG criteria, preguidelines (≤2015) vs postguidelines (>2015) comparison
- Reclassification by VarSome and ClinVar applying 2015 ACMG criteria
- Preguidelines (≤2015) vs postguidelines (>2015) comparison
Main finding
As reported in the abstract
| Group | Value | Variants of uncertain significance (VUS) | B/LB | Conflicting | Risk factor | Lacking entries |
|---|---|---|---|---|---|---|
| VarSome | 47.6% | 249 (26.7%) | 240 (25.7%) | |||
| ClinVar | 18.3% | 104 (11.1%) | 68 (7.3%) | 85 (9.1%) | 13 (1.4%) | 492 (52.7%) |
Value
VarSome47.6%
ClinVar18.3%
Variants of uncertain significance (VUS)
VarSome249 (26.7%)
ClinVar104 (11.1%)
B/LB
VarSome240 (25.7%)
ClinVar68 (7.3%)
Conflicting
VarSome— not stated in the abstract
ClinVar85 (9.1%)
Risk factor
VarSome— not stated in the abstract
ClinVar13 (1.4%)
Lacking entries
VarSome— not stated in the abstract
ClinVar492 (52.7%)
Further findings
Missense variants among VarSome classes
- Missense among VarSome P/LP
- 37.2%
- Missense among VarSome VUS
- 84.3%
Original publication
Overestimation of Pathogenic Variants in Idiopathic Hypogonadotropic Hypogonadism and Kallmann Syndrome. Endocr Pract. Published 30 January 2026. doi:10.
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