Submissions for variant NM_001126128.2(PROK2):c.163del (p.Ser54_Ile55insTer)

gnomAD frequency: 0.00013  dbSNP: rs554675432

Total submissions: 13

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Eurofins Ntd Llc (ga)	RCV000516187	SCV000343525	pathogenic	not provided	2016-08-01	criteria provided, single submitter	clinical testing
Genetic Services Laboratory, University of Chicago	RCV000003786	SCV000596588	pathogenic	Hypogonadotropic hypogonadism 4 with or without anosmia	2016-06-15	criteria provided, single submitter	clinical testing
Athena Diagnostics	RCV000516187	SCV000614789	pathogenic	not provided	2016-11-28	criteria provided, single submitter	clinical testing
Centre for Mendelian Genomics, University Medical Centre Ljubljana	RCV000003786	SCV001368421	pathogenic	Hypogonadotropic hypogonadism 4 with or without anosmia	2020-01-21	criteria provided, single submitter	clinical testing	This variant was classified as: Pathogenic. The following ACMG criteria were applied in classifying this variant: PVS1,PS1,PM2.
GeneDx	RCV000516187	SCV001817835	pathogenic	not provided	2023-03-06	criteria provided, single submitter	clinical testing	Nonsense 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: 18559922, 18682503, 18285834, 24423319, 17959774, 29419413, 29165578, 29022642, 31200363, 31589614, 23643382, 31980526, 36268624)
Labcorp Genetics (formerly Invitae), Labcorp	RCV000516187	SCV002247164	pathogenic	not provided	2023-11-07	criteria provided, single submitter	clinical testing	This sequence change creates a premature translational stop signal (p.Ile55*) in the PROK2 gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in PROK2 are known to be pathogenic (PMID: 17959774). This variant is present in population databases (rs554675432, gnomAD 0.02%). This premature translational stop signal has been observed in individuals with Kallmann syndrome (PMID: 17959774, 18285834, 18559922, 23643382). It has also been observed to segregate with disease in related individuals. This variant is also known as I55fsX1. ClinVar contains an entry for this variant (Variation ID: 3603). For these reasons, this variant has been classified as Pathogenic.
Mendelics	RCV000003786	SCV002518907	pathogenic	Hypogonadotropic hypogonadism 4 with or without anosmia	2022-05-04	criteria provided, single submitter	clinical testing
Laan Lab, Human Genetics Research Group, University of Tartu	RCV003991567	SCV004239169	pathogenic	Male infertility with azoospermia or oligozoospermia due to single gene mutation	2023-09-01	criteria provided, single submitter	research
Ambry Genetics	RCV004658957	SCV005153071	pathogenic	Inborn genetic diseases	2024-05-10	criteria provided, single submitter	clinical testing	The c.163delA (p.I55*) alteration, located in exon 2 (coding exon 2) of the PROK2 gene, consists of a deletion of one nucleotide at position 163. This changes the amino acid from an isoleucine (I) to a stop codon at amino acid position 55. This alteration is expected to result in loss of function by premature protein truncation or nonsense-mediated mRNA decay; however, loss-of-function of PROK2 has not been established as a mechanism of disease for autosomal dominant PROK2-related hypogonadotropic hypogonadism with or without anosmia. for autosomal recessive PROK2-related hypogonadotropic hypogonadism with or without anosmia; however, its clinical significance for autosomal dominant PROK2-related hypogonadotropic hypogonadism with or without anosmia is uncertain. Based on data from gnomAD, the c.163delA variant has an overall frequency of 0.011% (32/282872) total alleles studied. The highest observed frequency was 0.024% (31/129182) of European (non-Finnish) alleles. This variant has been identified in the homozygous state in individual(s) with features consistent with autosomal recessive PROK2-related hypogonadotropic hypogonadism with or without anosmia (Cassatella, 2018; Pitteloud, 2007; Miraoui, 2013; Leroy, 2008; Cole, 2008). This variant has also been reported in the heterozygous state in multiple individuals with features consistent with autosomal dominant PROK2-related hypogonadotropic hypogonadism with or without anosmia (Amato, 2019; Pierzchlewska, 2017; Abreu, 2008; Cannarella, 2023). Based on the available evidence, this alteration is classified as pathogenic.
OMIM	RCV000003786	SCV000023951	pathogenic	Hypogonadotropic hypogonadism 4 with or without anosmia	2008-09-01	no assertion criteria provided	literature only
Genome Diagnostics Laboratory, Amsterdam University Medical Center	RCV000516187	SCV001809562	pathogenic	not provided		no assertion criteria provided	clinical testing
Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	RCV000516187	SCV001958035	pathogenic	not provided		no assertion criteria provided	clinical testing
PreventionGenetics, part of Exact Sciences	RCV003892107	SCV004715212	pathogenic	PROK2-related disorder	2024-02-20	no assertion criteria provided	clinical testing	The PROK2 c.163delA variant is predicted to result in premature protein termination (p.Ile55*). This variant was reported in the homozygous state in individuals with Kallmann syndrome and hypogonadotropic hypogonadism (Pitteloud et al. 2007. PubMed ID: 17959774; Cole et al. 2008. PubMed ID: 18559922; Supplementary Table S3, Case #34, Miraoui et al. 2013. PubMed ID: 23643382). This variant has also been reported in the heterozygous state in individuals with normosmic congenital hypogonadotropic hypogonadism (ID 43 and 44, Amato et al. 2019. PubMed ID: 31200363). In vitro functional studies determined that this variant leads to loss of PROK2 activity (Pitteloud et al. 2007. PubMed ID: 17959774). This variant is reported in 0.024% of alleles in individuals of European (Non-Finnish) descent in gnomAD and is interpreted as pathogenic in the ClinVar database by multiple outside laboratories (https://www.ncbi.nlm.nih.gov/clinvar/variation/3603/). Nonsense variants in PROK2 are expected to be pathogenic. Taken together, this variant is interpreted as pathogenic.