ClinVar Genomic variation as it relates to human health
NM_144773.4(PROKR2):c.58del (p.His20fs)
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.
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(3); Likely pathogenic(4); Uncertain significance(3)
No data submitted for somatic clinical impact
No data submitted for oncogenicity
Variant Details
- Identifiers
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NM_144773.4(PROKR2):c.58del (p.His20fs)
Variation ID: 3452 Accession: VCV000003452.24
- Type and length
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Deletion, 1 bp
- Location
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Cytogenetic: 20p12.3 20: 5314312 (GRCh38) [ NCBI UCSC ] 20: 5294958 (GRCh37) [ NCBI UCSC ]
- Timeline in ClinVar
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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 Jul 2, 2015 Feb 20, 2024 Jun 10, 2023 - HGVS
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Nucleotide Protein Molecular
consequenceNM_144773.4:c.58del MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_658986.1:p.His20fs frameshift NM_144773.4:c.58delC MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
frameshift NM_144773.2:c.58delC NM_144773.3:c.58delC NC_000020.11:g.5314313del NC_000020.10:g.5294959del NG_008132.2:g.5058del - Protein change
- H20fs
- Other names
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- Canonical SPDI
- NC_000020.11:5314311:GG:G
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Functional
consequence HelpThe effect of the variant on RNA or protein function, based on experimental evidence from submitters.
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Global minor allele
frequency (GMAF) HelpThe 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.
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Allele frequency
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The frequency of the allele represented by this VCV record.
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- Comment on variant
Genes
Gene | OMIM | ClinGen Gene Dosage Sensitivity Curation |
Variation Viewer
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Links to Variation Viewer, a genome browser to view variation data from NCBI databases. |
Related variants | ||
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HI score
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The haploinsufficiency score for the gene, curated by ClinGen’s Dosage Sensitivity Curation task team. |
TS score
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The triplosensitivity score for the gene, curated by ClinGen’s Dosage Sensitivity Curation task team. |
Within gene
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The number of variants in ClinVar that are contained within this gene, with a link to view the list of variants. |
All
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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. |
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PROKR2 | - | - |
GRCh38 GRCh37 |
147 | 183 |
Conditions - Germline
Condition
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The condition for this variant-condition (RCV) record in ClinVar. |
Classification
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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
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The most recent date that a submitter evaluated this variant for the condition. |
Variation/condition record
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The RCV accession number, with most recent version number, for the variant-condition record, with a link to the RCV web page. |
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Conflicting interpretations of pathogenicity (6) |
criteria provided, conflicting classifications
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Jun 17, 2022 | RCV000022409.16 | |
Pathogenic/Likely pathogenic (2) |
criteria provided, multiple submitters, no conflicts
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Jun 10, 2023 | RCV000479789.9 | |
Likely pathogenic (1) |
criteria provided, single submitter
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Jan 30, 2015 | RCV000623831.3 | |
Uncertain significance (1) |
criteria provided, single submitter
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Jan 21, 2020 | RCV001818122.4 | |
Pathogenic (1) |
criteria provided, single submitter
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Jan 27, 2022 | RCV002288460.2 |
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
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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
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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
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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. |
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Uncertain significance
(Oct 06, 2021)
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criteria provided, single submitter
Method: clinical testing
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Hypogonadotropic hypogonadism 3 with or without anosmia
Affected status: unknown
Allele origin:
unknown
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Laboratory of Medical Genetics, National & Kapodistrian University of Athens
Accession: SCV001976882.1
First in ClinVar: Oct 16, 2021 Last updated: Oct 16, 2021 |
Comment:
PM2
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Uncertain significance
(Jan 21, 2020)
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criteria provided, single submitter
Method: clinical testing
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not specified
Affected status: no
Allele origin:
germline
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Genetic Services Laboratory, University of Chicago
Accession: SCV002067427.1
First in ClinVar: Jan 29, 2022 Last updated: Jan 29, 2022 |
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Pathogenic
(Jun 17, 2022)
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criteria provided, single submitter
Method: clinical testing
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Hypogonadotropic hypogonadism 3 with or without anosmia
Affected status: unknown
Allele origin:
germline
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Women's Health and Genetics/Laboratory Corporation of America, LabCorp
Accession: SCV002555983.1
First in ClinVar: Aug 03, 2022 Last updated: Aug 03, 2022 |
Comment:
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 … (more)
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. (less)
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Pathogenic
(Jan 27, 2022)
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criteria provided, single submitter
Method: clinical testing
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Hypogonadotropic hypogonadism 2 with or without anosmia
Affected status: yes
Allele origin:
germline
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MGZ Medical Genetics Center
Accession: SCV002581196.1
First in ClinVar: Oct 15, 2022 Last updated: Oct 15, 2022
Comment:
ACMG criteria applied: PVS1, PS4_MOD, PM2_SUP
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Number of individuals with the variant: 3
Sex: female
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Likely pathogenic
(Jan 30, 2015)
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criteria provided, single submitter
Method: clinical testing
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Hereditary disease
Affected status: yes
Allele origin:
germline
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Ambry Genetics
Accession: SCV000740792.2
First in ClinVar: Apr 15, 2018 Last updated: Dec 11, 2022 |
Comment:
Lines of evidence used in support of classification: CANDIDATE: Alteration(s) of Potential Clinical Relevance Detected
Clinical Features:
Gastrointestinal (child onset) (present) , Genitourinary (child onset) (present)
Family history: yes
Sex: male
Ethnicity/Population group: European-origin
Segregation observed: yes
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Likely pathogenic
(Nov 05, 2020)
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criteria provided, single submitter
Method: clinical testing
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Hypogonadotropic hypogonadism 3 with or without anosmia
Affected status: yes
Allele origin:
paternal
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Victorian Clinical Genetics Services, Murdoch Childrens Research Institute
Accession: SCV003921899.1
First in ClinVar: May 06, 2023 Last updated: May 06, 2023 |
Comment:
0103 - Dominant negative and loss of function are known mechanisms of disease in this gene and are associated with hypogonadotropic hypogonadism 3 with or … (more)
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 (less)
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Likely pathogenic
(Jun 24, 2020)
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criteria provided, single submitter
Method: clinical testing
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Hypogonadotropic hypogonadism 3 with or without anosmia
Affected status: unknown
Allele origin:
germline
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Revvity Omics, Revvity
Accession: SCV002024750.3
First in ClinVar: Nov 29, 2021 Last updated: Feb 04, 2024 |
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Pathogenic
(Jun 10, 2023)
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criteria provided, single submitter
Method: clinical testing
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not provided
Affected status: unknown
Allele origin:
germline
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Invitae
Accession: SCV001413363.4
First in ClinVar: Jul 16, 2020 Last updated: Feb 20, 2024 |
Comment:
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 … (more)
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). (less)
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Uncertain significance
(May 20, 2019)
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criteria provided, single submitter
Method: clinical testing
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Hypogonadotropic hypogonadism 3 with or without anosmia
Affected status: yes
Allele origin:
unknown
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Centre for Mendelian Genomics, University Medical Centre Ljubljana
Accession: SCV001369424.2
First in ClinVar: Jul 04, 2020 Last updated: Dec 12, 2020 |
Comment:
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 … (more)
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. (less)
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Likely pathogenic
(Feb 18, 2022)
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criteria provided, single submitter
Method: clinical testing
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Not Provided
Affected status: yes
Allele origin:
germline
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GeneDx
Accession: SCV000567903.6
First in ClinVar: Apr 27, 2017 Last updated: Mar 04, 2023 |
Comment:
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 … (more)
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) (less)
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Pathogenic
(Oct 20, 2006)
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no assertion criteria provided
Method: literature only
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HYPOGONADOTROPIC HYPOGONADISM 3 WITH ANOSMIA
Affected status: not provided
Allele origin:
germline
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OMIM
Accession: SCV000043094.4
First in ClinVar: Apr 04, 2013 Last updated: Jul 02, 2015 |
Comment on evidence:
In affected members of a family with Kallmann syndrome (HH3; 244200), Dode et al. (2006) identified heterozygosity for a 1-bp deletion (58delC) in exon 1 … (more)
In affected members of a family with Kallmann syndrome (HH3; 244200), Dode et al. (2006) identified heterozygosity for a 1-bp deletion (58delC) in exon 1 of the PROKR2 gene, causing a frameshift resulting in a premature termination codon (20fsTer43). In another family with Kallmann syndrome, they found the same mutation in compound heterozygous state with a 969G-A transition resulting in an M323I substitution (607123.0005). (less)
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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. |
Citations for germline classification of this variant
HelpTitle | Author | Journal | Year | Link |
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Kisspeptin-54 Accurately Identifies Hypothalamic Gonadotropin-Releasing Hormone Neuronal Dysfunction in Men with Congenital Hypogonadotropic Hypogonadism. | Abbara A | Neuroendocrinology | 2021 | PMID: 33227799 |
Germline prokineticin receptor 2 (PROKR2) variants associated with central hypogonadism cause differental modulation of distinct intracellular pathways. | Libri DV | The Journal of clinical endocrinology and metabolism | 2014 | PMID: 24276467 |
Greater prevalence of PROKR2 mutations in Kallmann syndrome patients from the Maghreb than in European patients. | Sarfati J | European journal of endocrinology | 2013 | PMID: 24031091 |
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 |
PROK2/PROKR2 Signaling and Kallmann Syndrome. | Dodé C | Frontiers in endocrinology | 2013 | PMID: 23596439 |
Prioritizing genetic testing in patients with Kallmann syndrome using clinical phenotypes. | Costa-Barbosa FA | The Journal of clinical endocrinology and metabolism | 2013 | PMID: 23533228 |
Variations in PROKR2, but not PROK2, are associated with hypopituitarism and septo-optic dysplasia. | McCabe MJ | The Journal of clinical endocrinology and metabolism | 2013 | PMID: 23386640 |
SEMA3A, a gene involved in axonal pathfinding, is mutated in patients with Kallmann syndrome. | Hanchate NK | PLoS genetics | 2012 | PMID: 22927827 |
PROKR2 variants in multiple hypopituitarism with pituitary stalk interruption. | Reynaud R | The Journal of clinical endocrinology and metabolism | 2012 | PMID: 22466334 |
Expression of PROKR1 and PROKR2 in human enteric neural precursor cells and identification of sequence variants suggest a role in HSCR. | Ruiz-Ferrer M | PloS one | 2011 | PMID: 21858136 |
Oligogenic basis of isolated gonadotropin-releasing hormone deficiency. | Sykiotis GP | Proceedings of the National Academy of Sciences of the United States of America | 2010 | PMID: 20696889 |
A comparative phenotypic study of kallmann syndrome patients carrying monoallelic and biallelic mutations in the prokineticin 2 or prokineticin receptor 2 genes. | Sarfati J | The Journal of clinical endocrinology and metabolism | 2010 | PMID: 20022991 |
PROKR2 missense mutations associated with Kallmann syndrome impair receptor signalling activity. | Monnier C | Human molecular genetics | 2009 | PMID: 18826963 |
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 |
Kallmann syndrome: mutations in the genes encoding prokineticin-2 and prokineticin receptor-2. | Dodé C | PLoS genetics | 2006 | PMID: 17054399 |
Identification of two prokineticin cDNAs: recombinant proteins potently contract gastrointestinal smooth muscle. | Li M | Molecular pharmacology | 2001 | PMID: 11259612 |
The genetic and clinical heterogeneity of gonadotropin-releasing hormone deficiency in the human. | Waldstreicher J | The Journal of clinical endocrinology and metabolism | 1996 | PMID: 8954047 |
Failure of cultured human T-cell lymphoid lines to stimulate in mixed leukocyte culture. | Royston I | Journal of the National Cancer Institute | 1974 | PMID: 4276467 |
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Text-mined citations for rs587777834 ...
HelpRecord last updated May 08, 2024
This date represents the last time this VCV record was updated. The update may be due to an update to one of the included submitted records (SCVs), or due to an update that ClinVar made to the variant such as adding HGVS expressions or a rs number. So this date may be different from the date of the “most recent submission” reported at the top of this page.
NCBI staff reviewed the sequence information reported in PubMed 17054399 Figure S1 to determine the location of this allele on the current reference sequence.