ClinVar Genomic variation as it relates to human health
NM_144773.4(PROKR2):c.563C>T (p.Ser188Leu)
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(1); Likely pathogenic(3); Uncertain significance(1)
No data submitted for somatic clinical impact
No data submitted for oncogenicity
Variant Details
- Identifiers
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NM_144773.4(PROKR2):c.563C>T (p.Ser188Leu)
Variation ID: 180158 Accession: VCV000180158.6
- Type and length
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single nucleotide variant, 1 bp
- Location
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Cytogenetic: 20p12.3 20: 5302632 (GRCh38) [ NCBI UCSC ] 20: 5283278 (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 Feb 2, 2015 Feb 20, 2024 Nov 28, 2023 - HGVS
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Nucleotide Protein Molecular
consequenceNM_144773.4:c.563C>T MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_658986.1:p.Ser188Leu missense NC_000020.11:g.5302632G>A NC_000020.10:g.5283278G>A NG_008132.2:g.16738C>T Q8NFJ6:p.Ser188Leu - Protein change
- S188L
- Other names
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- Canonical SPDI
- NC_000020.11:5302631:G:A
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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
Help
The frequency of the allele represented by this VCV record.
The Genome Aggregation Database (gnomAD), exomes 0.00001
Exome Aggregation Consortium (ExAC) 0.00002
The Genome Aggregation Database (gnomAD) 0.00002
Trans-Omics for Precision Medicine (TOPMed) 0.00005
NHLBI Exome Sequencing Project (ESP) Exome Variant Server 0.00008
1000 Genomes Project 30x 0.00031
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 | ||
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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
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. |
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PROKR2 | - | - |
GRCh38 GRCh37 |
147 | 183 |
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. |
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Likely pathogenic (1) |
criteria provided, single submitter
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Nov 1, 2014 | RCV000156965.1 | |
Likely pathogenic (2) |
criteria provided, multiple submitters, no conflicts
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May 22, 2022 | RCV002250579.2 | |
Conflicting interpretations of pathogenicity (2) |
criteria provided, conflicting classifications
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Nov 28, 2023 | RCV002505183.4 |
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. |
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Likely pathogenic
(Nov 01, 2014)
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criteria provided, single submitter
Method: case-control
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Hypogonadotrophic hypogonadism
Affected status: yes
Allele origin:
maternal
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Chan Lab, Boston Children's Hospital
Accession: SCV000206686.2
First in ClinVar: Feb 02, 2015 Last updated: Feb 02, 2015 |
Number of individuals with the variant: 1
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Likely pathogenic
(May 22, 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: yes
Allele origin:
germline
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3billion
Accession: SCV002521847.1
First in ClinVar: Jun 03, 2022 Last updated: Jun 03, 2022 |
Comment:
The variant is observed at an extremely low frequency in the gnomAD v2.1.1 dataset (total allele frequency: 0.001%). Missense changes are a common disease-causing mechanism. … (more)
The variant is observed at an extremely low frequency in the gnomAD v2.1.1 dataset (total allele frequency: 0.001%). Missense changes are a common disease-causing mechanism. Functional studies provide strong evidence of the variant having a damaging effect on the gene or gene product (PMID: 18559922). In silico tool predictions suggest damaging effect of the variant on gene or gene product (REVEL: 0.52; 3Cnet: 0.88). Same nucleotide change resulting in same amino acid change has been previously reported to be associated with PROKR2 related disorder (ClinVar ID: VCV000180158 / PMID: 18559922). Therefore, this variant is classified as likely pathogenic according to the recommendation of ACMG/AMP guideline. (less)
Clinical Features:
Intellectual disability, mild (present) , Microscopic hematuria (present) , Obesity (present) , Hypogonadotropic hypogonadism (present) , Micropenis (present) , Panhypopituitarism (present)
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Likely pathogenic
(Feb 02, 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:
unknown
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Fulgent Genetics, Fulgent Genetics
Accession: SCV002808496.1
First in ClinVar: Dec 31, 2022 Last updated: Dec 31, 2022 |
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Pathogenic
(Jul 02, 2019)
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criteria provided, single submitter
Method: clinical testing
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not provided
Affected status: unknown
Allele origin:
unknown
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Athena Diagnostics Inc
Accession: SCV002817207.1
First in ClinVar: Dec 31, 2022 Last updated: Dec 31, 2022 |
Comment:
This variant is statistically more frequent in affected individuals than in the general population and/or healthy controls (PMID: 28209183, 18559922, http://gnomad.broadinstitute.org). Assessment of experimental evidence … (more)
This variant is statistically more frequent in affected individuals than in the general population and/or healthy controls (PMID: 28209183, 18559922, http://gnomad.broadinstitute.org). Assessment of experimental evidence suggests this variant reduces the downstream signaling effects of this receptor, thus disrupting the normal function of the protein (PMID: 18559922, 29161432).This observation is not an independent occurrence and has been identified in the same individual by RCIGM, the other laboratory participating in the GEMINI study. (less)
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Uncertain significance
(Nov 28, 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: SCV003241475.2
First in ClinVar: Feb 07, 2023 Last updated: Feb 20, 2024 |
Comment:
This sequence change replaces serine, which is neutral and polar, with leucine, which is neutral and non-polar, at codon 188 of the PROKR2 protein (p.Ser188Leu). … (more)
This sequence change replaces serine, which is neutral and polar, with leucine, which is neutral and non-polar, at codon 188 of the PROKR2 protein (p.Ser188Leu). This variant is present in population databases (rs376239580, gnomAD 0.01%). This missense change has been observed in individual(s) with absent puberty, disorders of sex development, hypogonadotropic hypogonadism, Kallman syndrome, and/or micropenis (PMID: 18559922, 27899157, 28209183, 28754744, 31781422, 33587123, 34348883). ClinVar contains an entry for this variant (Variation ID: 180158). 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) has been performed at Invitae for this missense variant, however the output from this modeling did not meet the statistical confidence thresholds required to predict the impact of this variant on PROKR2 protein function. Experimental studies have shown that this missense change affects PROKR2 function (PMID: 18559922, 24830383, 29161432, 36694982). In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. (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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A functional spectrum of PROKR2 mutations identified in isolated hypogonadotropic hypogonadism. | Wang X | Human molecular genetics | 2023 | PMID: 36694982 |
Genetic Profiles and Three-year Follow-up Study of Chinese Males With Congenital Hypogonadotropic Hypogonadism. | Zhang L | The journal of sexual medicine | 2021 | PMID: 34348883 |
Novel Variant Findings and Challenges Associated With the Clinical Integration of Genomic Testing: An Interim Report of the Genomic Medicine for Ill Neonates and Infants (GEMINI) Study. | Maron JL | JAMA pediatrics | 2021 | PMID: 33587123 |
Parallel Multi-Gene Panel Testing for Diagnosis of Idiopathic Hypogonadotropic Hypogonadism/Kallmann Syndrome. | Senthilraja M | Case reports in genetics | 2019 | PMID: 31781422 |
Modeling mutant/wild-type interactions to ascertain pathogenicity of PROKR2 missense variants in patients with isolated GnRH deficiency. | Cox KH | Human molecular genetics | 2018 | PMID: 29161432 |
KLB, encoding β-Klotho, is mutated in patients with congenital hypogonadotropic hypogonadism. | Xu C | EMBO molecular medicine | 2017 | PMID: 28754744 |
Variants in congenital hypogonadotrophic hypogonadism genes identified in an Indonesian cohort of 46,XY under-virilised boys. | Ayers KL | Human genomics | 2017 | PMID: 28209183 |
Disorders of sex development: insights from targeted gene sequencing of a large international patient cohort. | Eggers S | Genome biology | 2016 | PMID: 27899157 |
Biased signaling through G-protein-coupled PROKR2 receptors harboring missense mutations. | Sbai O | FASEB journal : official publication of the Federation of American Societies for Experimental Biology | 2014 | PMID: 24830383 |
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 |
Text-mined citations for rs376239580 ...
HelpRecord last updated Feb 28, 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.