Submissions for variant NM_144773.4(PROKR2):c.533G>C (p.Trp178Ser)

gnomAD frequency: 0.00003  dbSNP: rs201835496

Total submissions: 6

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Soonchunhyang University Bucheon Hospital, Soonchunhyang University Medical Center	RCV000144714	SCV000267467	likely pathogenic	Hypogonadotropic hypogonadism 3 with or without anosmia	2016-03-18	criteria provided, single submitter	reference population
Labcorp Genetics (formerly Invitae), Labcorp	RCV000870421	SCV001011918	likely benign	not provided	2024-07-15	criteria provided, single submitter	clinical testing
GeneDx	RCV000870421	SCV005201985	likely pathogenic	not provided	2023-07-14	criteria provided, single submitter	clinical testing	Identified in patients with hypogonadotropic hypogonadism or hypospadias in published literature who inherited the variant from an unaffected parent, suggesting reduced penetrance or oligogenic inheritance (Aoyama et al., 2017; Zhang et al., 2019; Zhang et al., 2021; Liu et al., 2022); Identified in patients with potentially causative variants in other genes and in one patient with a second PROKR2 variant on the opposite allele (in trans) in published literature, supporting oligogenic or recessive inheritance (Zhao et al., 2019; Zhang et al., 2019; Chen et al., 2020; Liu et al., 2022); Published functional studies demonstrate a damaging effect on transport to the plasma membrane, MAPK signaling, and mobilization of intracellular calcium (Monnier at al., 2009; Cox et al., 2018; Song et al., 2022); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Observed de novo without confirmed parentage in multiple unrelated patients with Kallmann syndrome or normosmic idiopathic hypogonadotropic hypogonadism in published literature (Liu et al., 2022); This variant is associated with the following publications: (PMID: 22995991, 34489640, 33120852, 34653508, 35669683, 33983622, 18559922, 36317218, 35207461, 36123965, 19707180, 34636164, 35922219, 37122876, 26088945, 24753254, 33968656, 21736917, 32155719, 21664414, 20502053, 35173048, 29161432, 18826963, 26141714, 17054399, 28915117, 30098700, 30487145, 28295047, 33208564, 31219235, 30216942, 32171629, 35090434, 30576231)
Victorian Clinical Genetics Services, Murdoch Childrens Research Institute	RCV000144714	SCV005399249	likely benign	Hypogonadotropic hypogonadism 3 with or without anosmia	2020-10-19	criteria provided, single submitter	clinical testing	Based on the classification scheme VCGS_Germline_v1.3.3, this variant is classified as likely benign. Following criteria are met: 0103 - Dominant negative and loss of function are known mechanisms of disease in this gene and are associated with Kallmann syndrome (PMID: 29161432, PMID: 18826963). (I) 0108 - This gene is associated with both recessive and dominant disease. Heterozygotes, compound heterozygotes and homozygous have all been reported and digenic inheritance is also suggested (OMIM). (I) 0112 - The condition associated with this gene has been indicated to have incomplete penetrance. Heterozygotes have been reported as asymptomatic carriers (OMIM). (I) 0200 - Variant is predicted to result in a missense amino acid change from tryptophan to serine. (I) 0251 - This variant is heterozygous. (I) 0308 - Population frequency for this variant is out of keeping with known incidence of Kallmann syndrome. The gnomAD frequency data is skewed towards the East Asian population, with 56 out of 58 global heterozygotes being observed in this subpopulation. This variant is present in 0.3% of the East Asian gnomAD population. (SB) 0501 - Missense variant consistently predicted to be damaging by multiple in silico tools or highly conserved with a major amino acid change. (SP) 0600 - Variant is located in the annotated 7-transmembrane receptor (NCBI_Conserved_Domains, DECIPHER, RCSB-PDB). (I) 0705 - No missense variants affecting the same amino acid have previous evidence for pathogenicity. (I) 0808 - Previous reports of pathogenicity for this variant are conflicting. This variant has been reported in Kallmann syndrome patients (PMID: 30576231, PMID: 30216942), however, it has also been reported in unaffected individuals (PMID: 30487145) and in patients with pathogenic variants in other genes (PMID: 31219235). ClinVar has conflicting interpretation of pathogenicity for this variant, however, the most recent entry is likely benign. To our knowledge, this variant has only been reported in patients from the East Asian region, a region in which this variant is present in the general population. (I) 1010 - Functional evidence for this variant is inconclusive. HEK cell functional analysis indicates that this variant may impair cell surface-targeting of the receptor (PMID: 18826963). (I) 1208 - Inheritance information for this variant is not currently available in this individual. (I) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign
Juno Genomics, Hangzhou Juno Genomics, Inc	RCV000144714	SCV005416757	uncertain significance	Hypogonadotropic hypogonadism 3 with or without anosmia		criteria provided, single submitter	clinical testing	BS1+PS3_Moderate+PS4+PM6+PP4
OMIM	RCV000144714	SCV000190708	pathogenic	Hypogonadotropic hypogonadism 3 with or without anosmia	2009-01-01	no assertion criteria provided	literature only