Total submissions: 2
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| Victorian Clinical Genetics Services, |
RCV000015488 | SCV005398657 | pathogenic | Gonadotropin-independent familial sexual precocity | 2022-02-02 | criteria provided, single submitter | clinical testing | Based on the classification scheme VCGS_Germline_v1.3.4, this variant is classified as Pathogenic. Following criteria are met: 0103 - Loss of function and gain of function are known mechanisms of disease in this gene and are associated with Leydig cell hypoplasia (MIM#238320) and precocious puberty, male, (MIM#176410); respectively (Huhtaniemi 2018). (I) 0108 - This gene is associated with both recessive and dominant disease. Variants associated with autosomal dominant condition are mostly located within the sixth transmembrane domain and C-terminal region of the third intracellular loop (Huhtaniemi 2018). (I) 0115 - Variants in this gene are known to have variable expressivity. Loss-of-function variants associated with Leydig cell hypoplasia (MIM#238320) can result in variable clinical severity (Huhtaniemi 2018). (I) 0200 - Variant is predicted to result in a missense amino acid change from alanine to valine. (I) 0251 - This variant is heterozygous. (I) 0301 - Variant is absent from gnomAD (both v2 and v3). (SP) 0309 - An alternative amino acid change at the same position has been observed in gnomAD (v3: 1 heterozygote, 0 homozygotes). (I) 0502 - Missense variant with conflicting in silico predictions and uninformative conservation. (I) 0602 - Variant is located in a hotspot region or cluster of pathogenic variants (DECIPHER). (SP) 0705 - No comparable missense variants have previous evidence for pathogenicity. (I) 0802 - This variant has moderate previous evidence of pathogenicity in unrelated individuals. It has been identified in at least three males with precocious puberty, two of whom were heterozygotes. It was noted that the homozygote did not differ in his clinical and hormonal data, except for accelerated bone age (PMID: 11134146). (SP) 0905 - No published segregation evidence has been identified for this variant. (I) 1002 - This variant has moderate functional evidence supporting abnormal protein function. In vitro assays demonstrated increased in cAMP levels with expression of mutant protein (PMID: 7629248). (SP) 1208 - Inheritance information for this variant is not currently available in this individual. (I) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign |
| OMIM | RCV000015488 | SCV000035753 | pathogenic | Gonadotropin-independent familial sexual precocity | 2000-12-01 | no assertion criteria provided | literature only |