ClinVar Genomic variation as it relates to human health
NM_144773.4(PROKR2):c.254G>T (p.Arg85Leu)
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.
Uncertain significance(2); Likely benign(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.254G>T (p.Arg85Leu)
Variation ID: 338863 Accession: VCV000338863.8
- Type and length
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single nucleotide variant, 1 bp
- Location
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Cytogenetic: 20p12.3 20: 5314116 (GRCh38) [ NCBI UCSC ] 20: 5294762 (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 Dec 6, 2016 Feb 20, 2024 Oct 3, 2023 - HGVS
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Nucleotide Protein Molecular
consequenceNM_144773.4:c.254G>T MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_658986.1:p.Arg85Leu missense NC_000020.11:g.5314116C>A NC_000020.10:g.5294762C>A NG_008132.2:g.5254G>T - Protein change
- R85L
- Other names
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- Canonical SPDI
- NC_000020.11:5314115:C: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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0.00060 (A)
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Allele frequency
Help
The frequency of the allele represented by this VCV record.
Trans-Omics for Precision Medicine (TOPMed) 0.00041
1000 Genomes Project 0.00060
1000 Genomes Project 30x 0.00062
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
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
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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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Likely benign (1) |
criteria provided, single submitter
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Apr 27, 2017 | RCV000305149.5 | |
Uncertain significance (1) |
criteria provided, single submitter
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Jun 10, 2019 | RCV001281470.1 | |
Uncertain significance (1) |
criteria provided, single submitter
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Oct 3, 2023 | RCV002520022.2 |
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
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 benign
(Apr 27, 2017)
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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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Illumina Laboratory Services, Illumina
Accession: SCV000434479.3
First in ClinVar: Dec 06, 2016 Last updated: May 31, 2020 |
Comment:
This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, … (more)
This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). Publications were found based on this search. The evidence from the literature, in combination with allele frequency data from public databases where available, was sufficient to determine this variant is unlikely to cause disease. Therefore, this variant is classified as likely benign. (less)
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Uncertain significance
(Jun 10, 2019)
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criteria provided, single submitter
Method: clinical testing
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Seizure
(Autosomal dominant inheritance)
Affected status: yes
Allele origin:
maternal
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New York Genome Center
Study: CSER-NYCKidSeq
Accession: SCV001468778.1 First in ClinVar: Jan 17, 2021 Last updated: Jan 17, 2021 |
Comment:
The inherited c.254G>T (p.Arg85Leu) variant in PROKR2 substitutes a highly conserved Arginine for Leucine at amino acid 85/385 (coding exon 2/3). It is found in … (more)
The inherited c.254G>T (p.Arg85Leu) variant in PROKR2 substitutes a highly conserved Arginine for Leucine at amino acid 85/385 (coding exon 2/3). It is found in gnomAD (7 heterozygous individuals, 0 homozygous individuals, allele frequency: 2.2e-4) and ExAC (38 heterozygous individuals, 0 homozygous individuals; allele frequency: 3.13e-4). In silico algorithms predict that this variant is Deleterious (Provean; score: -5.97) and Damaging (SIFT; score: 0.000) to the function of the canonical transcript. This variant is reported in ClinVar with a single submission lacking supporting evidence as Likely Benign (VarID:338863), however different amino acid changes at the same residuehave been reported as Pathogenic, Likely Pathogenic, or as a Variant of Uncertain Significance (p.Arg85His; p.Arg85Gly; Arg85Cys). The Arg85 residue is at the first intracellular loop, and functional studies have suggested that the p.Arg85Leu variant has a mild G-protein coupling defectas well as reduced quantity of protein present at the cell surface [PMID: 24830383].This variant has been identified inindividuals in the literature with Kallmann syndrome or pituitary hormone deficiency [PMID: 24031091; PMID: 23386640]. The inherited c.254G>T (p.Arg85Leu) variant is reported here as a Variant of Uncertain Significance. (less)
Segregation observed: no
Secondary finding: no
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Uncertain significance
(Oct 03, 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: SCV003237412.2
First in ClinVar: Feb 07, 2023 Last updated: Feb 20, 2024 |
Comment:
This sequence change replaces arginine, which is basic and polar, with leucine, which is neutral and non-polar, at codon 85 of the PROKR2 protein (p.Arg85Leu). … (more)
This sequence change replaces arginine, which is basic and polar, with leucine, which is neutral and non-polar, at codon 85 of the PROKR2 protein (p.Arg85Leu). This variant is present in population databases (rs74315418, gnomAD 0.05%). This missense change has been observed in individual(s) with PROKR2-related conditions (PMID: 20022991, 23386640, 31093944). ClinVar contains an entry for this variant (Variation ID: 338863). 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) performed at Invitae indicates that this missense variant is expected to disrupt PROKR2 protein function. Experimental studies are conflicting or provide insufficient evidence to determine the effect of this variant on PROKR2 function (PMID: 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 analysis of adult Slovenian patients with combined pituitary hormone deficiency. | Bajuk Studen K | Endocrine | 2019 | PMID: 31093944 |
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 |
FGFR1 and PROKR2 rare variants found in patients with combined pituitary hormone deficiencies. | Correa FA | Endocrine connections | 2015 | PMID: 25759380 |
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 |
PROK2/PROKR2 Signaling and Kallmann Syndrome. | Dodé C | Frontiers in endocrinology | 2013 | PMID: 23596439 |
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 |
Evidence of the importance of the first intracellular loop of prokineticin receptor 2 in receptor function. | Abreu AP | Molecular endocrinology (Baltimore, Md.) | 2012 | PMID: 22745195 |
The results of CHD7 analysis in clinically well-characterized patients with Kallmann syndrome. | Bergman JE | The Journal of clinical endocrinology and metabolism | 2012 | PMID: 22399515 |
Genetic overlap in Kallmann syndrome, combined pituitary hormone deficiency, and septo-optic dysplasia. | Raivio T | The Journal of clinical endocrinology and metabolism | 2012 | PMID: 22319038 |
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 |
A genetic basis for functional hypothalamic amenorrhea. | Caronia LM | The New England journal of medicine | 2011 | PMID: 21247312 |
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 |
Kallmann syndrome: mutations in the genes encoding prokineticin-2 and prokineticin receptor-2. | Dodé C | PLoS genetics | 2006 | PMID: 17054399 |
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Text-mined citations for rs74315418 ...
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.