VCV000003603.27 - ClinVar

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

Germline

Classification

The aggregate germline classification for this variant, typically for a monogenic or Mendelian disorder as in the ACMG/AMP guidelines, or for response to a drug. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the aggregate classification.

(13)

Stars represent the aggregate review status, or the level of review supporting the aggregate germline classification for this VCV record. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the review status. The number of submissions which contribute to this review status is shown in parentheses.

Pathogenic

criteria provided, multiple submitters, no conflicts

Somatic

No data submitted for somatic clinical impact

Somatic

No data submitted for oncogenicity

Variant Details

Identifiers

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

Variation ID: 3603 Accession: VCV000003603.27

Type and length

Deletion, 1 bp

Location

Cytogenetic: 3p13 3: 71781526 (GRCh38) [ NCBI UCSC ] 3: 71830677 (GRCh37) [ NCBI UCSC ]

Timeline in ClinVar

	First in ClinVar Help The date this variant first appeared in ClinVar with each type of classification.	Last submission Help The date of the most recent submission for each type of classification for this variant.	Last evaluated Help The most recent date that a submitter evaluated this variant for each type of classification.
Germline	Oct 27, 2014	Oct 8, 2024	May 10, 2024

HGVS

Nucleotide	Protein	Molecular consequence
NM_001126128.2:c.163del MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.	NP_001119600.1:p.Ser54_Ile55insTer	nonsense
NM_001126128.1:c.163delA
NM_021935.4:c.163del	NP_068754.1:p.Ser54_Ile55insTer	nonsense
NC_000003.12:g.71781526del
NC_000003.11:g.71830677del
NG_008275.1:g.8681del

... more HGVS ... less HGVS

Protein change

Other names

Canonical SPDI

NC_000003.12:71781525:T:

Functional consequence Help The effect of the variant on RNA or protein function, based on experimental evidence from submitters.

Global minor allele frequency (GMAF) Help The global minor allele frequency calculated by the 1000 Genomes Project. The minor allele at this location is indicated in parentheses and may be different from the allele represented by this VCV record.

Allele frequency Help The frequency of the allele represented by this VCV record.

Trans-Omics for Precision Medicine (TOPMed) 0.00009

Exome Aggregation Consortium (ExAC) 0.00011

The Genome Aggregation Database (gnomAD), exomes 0.00012

The Genome Aggregation Database (gnomAD) 0.00013

Links

ClinGen: CA252841 OMIM: 607002.0003 dbSNP: rs554675432 VarSome

Genes

Gene	OMIM	ClinGen Gene Dosage Sensitivity Curation		Variation Viewer Help Links to Variation Viewer, a genome browser to view variation data from NCBI databases.	Related variants
Gene	OMIM	HI score Help The haploinsufficiency score for the gene, curated by ClinGen’s Dosage Sensitivity Curation task team.	TS score Help The triplosensitivity score for the gene, curated by ClinGen’s Dosage Sensitivity Curation task team.		Within gene Help The number of variants in ClinVar that are contained within this gene, with a link to view the list of variants.	All Help The number of variants in ClinVar for this gene, including smaller variants within the gene and larger CNVs that overlap or fully contain the gene.
PROK2		-	-	GRCh38 GRCh37	76	95

Conditions - Germline

Condition Help The condition for this variant-condition (RCV) record in ClinVar.	Classification Help The aggregate germline classification for this variant-condition (RCV) record in ClinVar. The number of submissions that contribute to this aggregate classification is shown in parentheses. (# of submissions)	Review status Help The aggregate review status for this variant-condition (RCV) record in ClinVar. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the review status.	Last evaluated Help The most recent date that a submitter evaluated this variant for the condition.	Variation/condition record Help The RCV accession number, with most recent version number, for the variant-condition record, with a link to the RCV web page.
Hypogonadotropic hypogonadism 4 with or without anosmia	Pathogenic (4)	criteria provided, multiple submitters, no conflicts	May 4, 2022	RCV000003786.15
not provided	Pathogenic (6)	criteria provided, multiple submitters, no conflicts	Nov 7, 2023	RCV000516187.19
PROK2-related disorder	Pathogenic (1)	no assertion criteria provided	Feb 20, 2024	RCV003892107.2
Male infertility with azoospermia or oligozoospermia due to single gene mutation	Pathogenic (1)	criteria provided, single submitter	Sep 1, 2023	RCV003991567.1
Inborn genetic diseases	Pathogenic (1)	criteria provided, single submitter	May 10, 2024	RCV004658957.1

Submissions - Germline

Classification Help The submitted germline classification for each SCV record. (Last evaluated)	Review status Help Stars represent the review status, or the level of review supporting the submitted (SCV) record. This value is calculated by NCBI based on data from the submitter. Read our rules for calculating the review status. This column also includes a link to the submitter’s assertion criteria if provided, and the collection method. (Assertion criteria)	Condition Help The condition for the classification, provided by the submitter for this submitted (SCV) record. This column also includes the affected status and allele origin of individuals observed with this variant.	Submitter Help The submitting organization for this submitted (SCV) record. This column also includes the SCV accession and version number, the date this SCV first appeared in ClinVar, and the date that this SCV was last updated in ClinVar.	More information Help This column includes more information supporting the classification, including citations, the comment on classification, and detailed evidence provided as observations of the variant by the submitter.
Pathogenic (Jun 15, 2016)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Hypogonadotropic hypogonadism 4 with or without anosmia Affected status: yes Allele origin: germline	Genetic Services Laboratory, University of Chicago Accession: SCV000596588.1 First in ClinVar: Aug 27, 2017 Last updated: Aug 27, 2017
Pathogenic (Jan 21, 2020)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Hypogonadotropic hypogonadism 4 with or without anosmia Affected status: yes Allele origin: unknown	Centre for Mendelian Genomics, University Medical Centre Ljubljana Accession: SCV001368421.2 First in ClinVar: Jul 04, 2020 Last updated: Dec 12, 2020	Comment: This variant was classified as: Pathogenic. The following ACMG criteria were applied in classifying this variant: PVS1,PS1,PM2.
Pathogenic (May 04, 2022)	criteria provided, single submitter (Mendelics Assertion Criteria 2019) Method: clinical testing	Hypogonadotropic hypogonadism 4 with or without anosmia Affected status: unknown Allele origin: germline	Mendelics Accession: SCV002518907.1 First in ClinVar: May 28, 2022 Last updated: May 28, 2022
Pathogenic (Nov 07, 2023)	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015)) Method: clinical testing	not provided Affected status: unknown Allele origin: germline	Labcorp Genetics (formerly Invitae), Labcorp Accession: SCV002247164.3 First in ClinVar: Mar 28, 2022 Last updated: Feb 20, 2024	Publications: PubMed (4) PubMed: 17959774‚ 18285834‚ 18559922‚ 23643382 Comment: 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 … (more) 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. (less)
Pathogenic (May 10, 2024)	criteria provided, single submitter (Ambry Variant Classification Scheme 2023) Method: clinical testing	Inborn genetic diseases Affected status: unknown Allele origin: germline	Ambry Genetics Accession: SCV005153071.1 First in ClinVar: Aug 11, 2024 Last updated: Aug 11, 2024	Publications: PubMed (9) PubMed: 17959774‚ 18285834‚ 18559922‚ 18682503‚ 23643382‚ 29022642‚ 29419413‚ 31200363‚ 37108593 Comment: 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. … (more) 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. (less)
Pathogenic (Nov 28, 2016)	criteria provided, single submitter (Athena Diagnostics Criteria) Method: clinical testing	not provided Affected status: unknown Allele origin: germline	Athena Diagnostics Accession: SCV000614789.1 First in ClinVar: Dec 19, 2017 Last updated: Dec 19, 2017	Publications: PubMed (6) PubMed: 17959774‚ 24423319‚ 18285834‚ 23643382‚ 18559922‚ 18682503
Pathogenic (Aug 01, 2016)	criteria provided, single submitter (EGL Classification Definitions 2015) Method: clinical testing	not provided Affected status: unknown Allele origin: germline	Eurofins Ntd Llc (ga) Accession: SCV000343525.4 First in ClinVar: Dec 06, 2016 Last updated: Dec 15, 2018	Other databases http://www.egl-eurofins.com/emvc… http://www.egl-eurofins.com/emvclass/emvclass.php?approved_symbol=PROK2 Number of individuals with the variant: 1 Sex: mixed
Pathogenic (Mar 06, 2023)	criteria provided, single submitter (GeneDx Variant Classification Process June 2021) Method: clinical testing	Not Provided Affected status: yes Allele origin: germline	GeneDx Accession: SCV001817835.2 First in ClinVar: Sep 08, 2021 Last updated: Mar 18, 2023	Comment: 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 … (more) 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) (less)
Pathogenic (Sep 01, 2023)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: research	Male infertility with azoospermia or oligozoospermia due to single gene mutation (Autosomal dominant inheritance) Affected status: yes Allele origin: maternal	Laan Lab, Human Genetics Research Group, University of Tartu Accession: SCV004239169.1 First in ClinVar: Apr 15, 2024 Last updated: Apr 15, 2024	Publications: DOI: 10.1016/j.ajhg.2024.03.013 DOI: 10.1016/j.ajhg.2024.03.013 Family history: yes Sex: male
Pathogenic (Sep 01, 2008)	no assertion criteria provided Method: literature only	HYPOGONADOTROPIC HYPOGONADISM 4 WITH OR WITHOUT ANOSMIA Affected status: not provided Allele origin: germline	OMIM Accession: SCV000023951.3 First in ClinVar: Apr 04, 2013 Last updated: Oct 27, 2014	Publications: PubMed (3) PubMed: 17959774‚ 18285834‚ 18559922 Comment on evidence: In 2 brothers with anosmic hypogonadotropic hypogonadism and their sister who had normosmic idiopathic hypogonadotropic hypogonadism (HH4; 610628), Pitteloud et al. (2007) identified homozygosity for … (more) In 2 brothers with anosmic hypogonadotropic hypogonadism and their sister who had normosmic idiopathic hypogonadotropic hypogonadism (HH4; 610628), Pitteloud et al. (2007) identified homozygosity for a 1-bp deletion (163delA) in exon 2 of the PROK2 gene, predicted to result in a premature stop codon at amino acid 55 and a truncated protein of only 27 amino acids. An unaffected brother was heterozygous for the mutation. In vitro analysis of CHO cells expressing PROKR2 (607123) revealed that truncated PROK2 could not activate PROKR2 even at very high concentrations. Leroy et al. (2008) identified a homozygous 163delA mutation in a Swiss man with hypogonadotropic hypogonadism and complete anosmia. In a male patient with Kallmann syndrome, Cole et al. (2008) identified homozygosity for the 163delA mutation in the PROK2 gene. The patient did not go through puberty, and luteinizing hormone (LH; see 152780) was undetectable; his sense of smell was below the fifth percentile on olfactory testing, and MRI revealed absence of olfactory bulbs. He also had seizures. Functional analysis in CHO cells demonstrated complete loss of activation of PROKR2 (607123) with the truncated protein (I55fsTer1) even at very high concentrations. (less)
Pathogenic (-)	no assertion criteria provided Method: clinical testing	not provided Affected status: yes Allele origin: germline	Genome Diagnostics Laboratory, Amsterdam University Medical Center Study: VKGL Data-share Consensus Accession: SCV001809562.1 First in ClinVar: Aug 25, 2021 Last updated: Aug 25, 2021
Pathogenic (-)	no assertion criteria provided Method: clinical testing	not provided Affected status: yes Allele origin: germline	Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+ Additional submitter: Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen Study: VKGL Data-share Consensus Accession: SCV001958035.1 First in ClinVar: Oct 02, 2021 Last updated: Oct 02, 2021
Pathogenic (Feb 20, 2024)	no assertion criteria provided Method: clinical testing	PROK2-related condition Affected status: unknown Allele origin: germline	PreventionGenetics, part of Exact Sciences Accession: SCV004715212.2 First in ClinVar: Mar 16, 2024 Last updated: Oct 08, 2024	Comment: 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 … (more) 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. (less)
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Comment:

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.

Comment:

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.

Comment:

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)

Comment:

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.

Germline Functional Evidence

There is no functional evidence in ClinVar for this variation. If you have generated functional data for this variation, please consider submitting that data to ClinVar.

Comment:

Citations for germline classification of this variant

Title	Author	Journal	Year	Link
Toward clinical exomes in diagnostics and management of male infertility.	Lillepea K	American journal of human genetics	2024	DOI: 10.1016/j.ajhg.2024.03.013
Genetic Analysis of Patients with Congenital Hypogonadotropic Hypogonadism: A Case Series.	Cannarella R	International journal of molecular sciences	2023	PMID: 37108593
New genetic findings in a large cohort of congenital hypogonadotropic hypogonadism.	Amato LGL	European journal of endocrinology	2019	PMID: 31200363
Congenital hypogonadotropic hypogonadism and constitutional delay of growth and puberty have distinct genetic architectures.	Cassatella D	European journal of endocrinology	2018	PMID: 29419413
Induction of puberty with human chorionic gonadotropin (hCG) followed by reversal of hypogonadotropic hypogonadism in Kallmann syndrome.	Pierzchlewska MM	Endokrynologia Polska	2017	PMID: 29022642
Absence of central circadian pacemaker abnormalities in humans with loss of function mutation in prokineticin 2.	Balasubramanian R	The Journal of clinical endocrinology and metabolism	2014	PMID: 24423319
Mutations in FGF17, IL17RD, DUSP6, SPRY4, and FLRT3 are identified in individuals with congenital hypogonadotropic hypogonadism.	Miraoui H	American journal of human genetics	2013	PMID: 23643382
Loss-of-function mutations in the genes encoding prokineticin-2 or prokineticin receptor-2 cause autosomal recessive Kallmann syndrome.	Abreu AP	The Journal of clinical endocrinology and metabolism	2008	PMID: 18682503
Mutations in prokineticin 2 and prokineticin receptor 2 genes in human gonadotrophin-releasing hormone deficiency: molecular genetics and clinical spectrum.	Cole LW	The Journal of clinical endocrinology and metabolism	2008	PMID: 18559922
Biallelic mutations in the prokineticin-2 gene in two sporadic cases of Kallmann syndrome.	Leroy C	European journal of human genetics : EJHG	2008	PMID: 18285834
Loss-of-function mutation in the prokineticin 2 gene causes Kallmann syndrome and normosmic idiopathic hypogonadotropic hypogonadism.	Pitteloud N	Proceedings of the National Academy of Sciences of the United States of America	2007	PMID: 17959774
http://www.egl-eurofins.com/emvclass/emvclass.php?approved_symbol=PROK2	-	-	-	-
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Text-mined citations for rs554675432 ...

These citations are identified by LitVar using the rs number, so they may include citations for more than one variant at this location. Please review the LitVar results carefully for your variant of interest.

Record last updated Oct 13, 2024

ClinVar Genomic variation as it relates to human health

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

Variant Details

Genes

Conditions - Germline

Submissions - Germline

Germline Functional Evidence

Citations for germline classification of this variant

Text-mined citations for rs554675432 ...