Submissions for variant NM_144773.4(PROKR2):c.868C>T (p.Pro290Ser)

gnomAD frequency: 0.00010  dbSNP: rs149992595

Total submissions: 7

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Illumina Laboratory Services, Illumina	RCV001140169	SCV001300392	uncertain significance	Hypogonadotropic hypogonadism 3 with or without anosmia	2017-04-28	criteria provided, single submitter	clinical testing	This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). Publications were found based on this search. However, the evidence from the literature, in combination with allele frequency data from public databases where available, was not sufficient to rule this variant in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance.
GeneDx	RCV001565285	SCV001788603	uncertain significance	not provided	2020-06-19	criteria provided, single submitter	clinical testing	Identified in patients with Kallmann syndrome in published literature, in both the heterozygous and homozygous state (Dode et al., 2006; Sarfati et al., 2013); Observed in heterozygous state in clinically unaffected adults in published literature (Moya-Plana et al., 2013; Sarfati et al., 2013), and in at least one clinically unaffected adult relative of an individual referred for genetic testing at GeneDx; Published functional studies demonstrate a damaging effect due to impaired calcium signaling and cell surface targeting of the receptor (Monnier et al., 2009); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 17054399, 24031091, 23082007, 29161432, 23643382, 19707180, 18985070, 20022991, 21858136, 26088945, 24753254, 24830383, 20389090, 18826963)
Fulgent Genetics, Fulgent Genetics	RCV001140169	SCV002784301	uncertain significance	Hypogonadotropic hypogonadism 3 with or without anosmia	2024-02-09	criteria provided, single submitter	clinical testing
Labcorp Genetics (formerly Invitae), Labcorp	RCV001565285	SCV003786675	pathogenic	not provided	2023-10-03	criteria provided, single submitter	clinical testing	This sequence change replaces proline, which is neutral and non-polar, with serine, which is neutral and polar, at codon 290 of the PROKR2 protein (p.Pro290Ser). This variant is present in population databases (rs149992595, gnomAD 0.04%). This missense change has been observed in individuals with autosomal recessive Kallman syndrome (PMID: 24031091, 34539727). ClinVar contains an entry for this variant (Variation ID: 897086). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is expected to disrupt PROKR2 protein function. Experimental studies have shown that this missense change affects PROKR2 function (PMID: 18826963, 24753254, 24830383, 29161432, 35173048). For these reasons, this variant has been classified as Pathogenic.
Laan Lab, Human Genetics Research Group, University of Tartu	RCV003991586	SCV004239193	likely pathogenic	Male infertility with spermatogenesis disorder	2023-09-01	criteria provided, single submitter	research
NHS Central & South Genomic Laboratory Hub	RCV005253725	SCV005907145	uncertain significance	Hypogonadotropic hypogonadism	2025-04-09	criteria provided, single submitter	clinical testing
Genomics England Pilot Project, Genomics England	RCV001140169	SCV001760466	likely pathogenic	Hypogonadotropic hypogonadism 3 with or without anosmia		no assertion criteria provided	clinical testing