Submissions for variant NM_144773.4(PROKR2):c.58del (p.His20fs)

dbSNP: rs587777834

Total submissions: 11

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000479789	SCV000567903	likely pathogenic	not provided	2022-02-18	criteria provided, single submitter	clinical testing	Frameshift variant predicted to result in protein truncation or nonsense mediated decay in a gene for which loss-of-function is a known mechanism of disease; This variant is associated with the following publications: (PMID: 17054399, 23643382, 29778231, 31589614, 34426522, 24276467)
Ambry Genetics	RCV000623831	SCV000740792	likely pathogenic	Inborn genetic diseases	2015-01-30	criteria provided, single submitter	clinical testing	Lines of evidence used in support of classification: CANDIDATE: Alteration(s) of Potential Clinical Relevance Detected
Centre for Mendelian Genomics, University Medical Centre Ljubljana	RCV000022409	SCV001369424	uncertain significance	Hypogonadotropic hypogonadism 3 with or without anosmia	2019-05-20	criteria provided, single submitter	clinical testing	This variant was classified as: Uncertain significance. The available evidence on this variant's pathogenicity is insufficient or conflicting. The following ACMG criteria were applied in classifying this variant: PS1.
Invitae	RCV000479789	SCV001413363	pathogenic	not provided	2023-06-10	criteria provided, single submitter	clinical testing	For these reasons, this variant has been classified as Pathogenic. ClinVar contains an entry for this variant (Variation ID: 3452). This premature translational stop signal has been observed in individual(s) with Kallmann Syndrome (PMID: 17054399, 23643382, 24276467). This variant is present in population databases (rs587777834, gnomAD 0.02%). This sequence change creates a premature translational stop signal (p.His20Metfs*24) in the PROKR2 gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in PROKR2 are known to be pathogenic (PMID: 17054399, 18682503).
Laboratory of Medical Genetics, National & Kapodistrian University of Athens	RCV000022409	SCV001976882	uncertain significance	Hypogonadotropic hypogonadism 3 with or without anosmia	2021-10-06	criteria provided, single submitter	clinical testing	PM2
Revvity Omics, Revvity	RCV000022409	SCV002024750	likely pathogenic	Hypogonadotropic hypogonadism 3 with or without anosmia	2020-06-24	criteria provided, single submitter	clinical testing
Genetic Services Laboratory, University of Chicago	RCV001818122	SCV002067427	uncertain significance	not specified	2020-01-21	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000022409	SCV002555983	pathogenic	Hypogonadotropic hypogonadism 3 with or without anosmia	2022-06-17	criteria provided, single submitter	clinical testing	Variant summary: PROKR2 c.58delC (p.His20MetfsX24) results in a premature termination codon, predicted to cause a truncation of the encoded protein or absence of the protein due to nonsense mediated decay, which are commonly known mechanisms for disease. The variant allele was found at a frequency of 0.0001 in 251478 control chromosomes. This frequency does not allow conclusions about variant significance. c.58delC has been reported in the literature as a heterozygous genotype in individuals from a reportedly Kallman syndrome cohort (example, Sarfati_2013), idiopathic central hypogonadism (example, Libri_2014), congenital hypogonadotropic hypogonadism (example, Abbara_2021), Obesity (example, Libri_2014) and as a compound heterozygous genotype in at-least two individuals affected with hypogonadism and anosmia whose carrier mother reported as having only anosmia (example, Dode_2006). These data indicate that the variant is likely to be associated with disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Seven clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. Multiple laboratories reported the variant with conflicting assessments (VUS, n=3, Pathogenic/Likely pathogenic, n=4). Based on the evidence outlined above, the variant was classified as pathogenic.
MGZ Medical Genetics Center	RCV002288460	SCV002581196	pathogenic	Hypogonadotropic hypogonadism 2 with or without anosmia	2022-01-27	criteria provided, single submitter	clinical testing
Victorian Clinical Genetics Services, Murdoch Childrens Research Institute	RCV000022409	SCV003921899	likely pathogenic	Hypogonadotropic hypogonadism 3 with or without anosmia	2020-11-05	criteria provided, single submitter	clinical testing	0103 - Dominant negative and loss of function are known mechanisms of disease in this gene and are associated with hypogonadotropic hypogonadism 3 with or without anosmia (MONDO:0009482) (PMIDs: 18826963, 29161432). (I) 0108 - This gene is associated with both recessive and dominant disease. Heterozygous, compound heterozygous and homozygous variants have been reported several times in patients with hypogonadotropic hypogonadism 3 with or without anosmia (MONDO:0009482). (I) 0112 - The condition associated with this gene has incomplete penetrance (OMIM, PMID: 18682503). (I) 0201 - Variant is predicted to cause nonsense-mediated decay (NMD) and loss of protein (premature termination codon is located at least 54 nucleotides upstream of the final exon-exon junction). (SP) 0251 - This variant is heterozygous. (I) 0304 - Variant is present in gnomAD (v3) <0.01 (33 heterozygotes, 0 homozygotes). (SP) 0710 - Another NMD-predicted variant comparable to the one identified in this case has inconclusive previous evidence for pathogenicity. An individual with normosmic isolated hypogonadotropic hypogonadism was heterozygous for an NMD-predicted variant in the PROKR2 gene and also heterozygous for p.(Gln106Arg) in the GNRHR gene (PMID: 24276467). (I) 0808 - Previous reports of pathogenicity for this variant are conflicting. It has been reported in ClinVar, four times as pathogenic/likely pathogenic and three times as VUS by clinical testing laboratories. It has been reported in DECIPHER as uncertain significance in a heterozygous individual with hypospadias. It has also been reported as heterozygous in three affected individuals (PMIDs: 23643382, 24276467), as compound heterozygous in two affected siblings (PMIDs: 17054399, 20022991), and in at least one affected individual with unknown zygosity (PMID: 23533228). In addition, the variant has been reported as heterozygous in unaffected individuals (PMID: 31589614). (I) 1007 - No published functional evidence has been identified for this variant. (I) 1206 - This variant has been shown to be paternally inherited (by trio analysis). (I) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign
OMIM	RCV000022409	SCV000043094	pathogenic	Hypogonadotropic hypogonadism 3 with or without anosmia	2006-10-20	no assertion criteria provided	literature only