ClinVar Genomic variation as it relates to human health
NM_000406.3(GNRHR):c.436C>T (p.Pro146Ser)
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(6); Likely benign(1)
No data submitted for somatic clinical impact
No data submitted for oncogenicity
Variant Details
- Identifiers
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NM_000406.3(GNRHR):c.436C>T (p.Pro146Ser)
Variation ID: 449413 Accession: VCV000449413.20
- Type and length
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single nucleotide variant, 1 bp
- Location
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Cytogenetic: 4q13.2 4: 67753900 (GRCh38) [ NCBI UCSC ] 4: 68619618 (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 19, 2017 Mar 16, 2024 Feb 27, 2024 - HGVS
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Nucleotide Protein Molecular
consequenceNM_000406.3:c.436C>T MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_000397.1:p.Pro146Ser missense NM_001012763.2:c.436C>T NP_001012781.1:p.Pro146Ser missense NC_000004.12:g.67753900G>A NC_000004.11:g.68619618G>A NG_009293.1:g.7187C>T - Protein change
- P146S
- Other names
- -
- Canonical SPDI
- NC_000004.12:67753899: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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0.00060 (A)
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Allele frequency
Help
The frequency of the allele represented by this VCV record.
NHLBI Exome Sequencing Project (ESP) Exome Variant Server 0.00046
1000 Genomes Project 0.00060
The Genome Aggregation Database (gnomAD) 0.00076
1000 Genomes Project 30x 0.00078
Trans-Omics for Precision Medicine (TOPMed) 0.00092
The Genome Aggregation Database (gnomAD), exomes 0.00127
Exome Aggregation Consortium (ExAC) 0.00132
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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GNRHR | - | - |
GRCh38 GRCh37 |
179 | 207 |
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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Conflicting interpretations of pathogenicity (2) |
criteria provided, conflicting classifications
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Jan 18, 2024 | RCV000523077.11 | |
Uncertain significance (3) |
criteria provided, multiple submitters, no conflicts
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May 28, 2019 | RCV000765786.8 | |
Uncertain significance (1) |
criteria provided, single submitter
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Jan 7, 2020 | RCV001821457.4 | |
Uncertain significance (1) |
criteria provided, single submitter
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Feb 27, 2024 | RCV003935381.1 |
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. |
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Uncertain significance
(Oct 31, 2018)
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criteria provided, single submitter
Method: clinical testing
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Hypogonadotropic hypogonadism 7 with or without anosmia
Affected status: unknown
Allele origin:
unknown
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Fulgent Genetics, Fulgent Genetics
Accession: SCV000897175.1
First in ClinVar: Mar 31, 2019 Last updated: Mar 31, 2019 |
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Uncertain significance
(Jul 19, 2017)
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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: SCV000617556.2
First in ClinVar: Dec 19, 2017 Last updated: Dec 19, 2017 |
Comment:
The P146S variant has been published previously in patients with IHH, but only in the heterozygous state to our knowledge (Vagenakis et al., 2005; Sykiotis … (more)
The P146S variant has been published previously in patients with IHH, but only in the heterozygous state to our knowledge (Vagenakis et al., 2005; Sykiotis et al., 2010; Gianetti et al., 2012). The variant is observed in 69/11350 (0.61%) alleles from individuals of Latino background in the ExAC dataset (Lek et al., 2016). P146S is a non-conservative amino acid substitution, which is likely to impact secondary protein structure as these residues differ in polarity, charge, size and/or other properties. This substitution occurs at a position that is conserved across species, and in silico analysis predicts this variant is probably damaging to the protein structure/function. In summary, based on the currently available information, it is unclear whether this variant is a pathogenic variant or a rare benign variant. (less)
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Uncertain significance
(May 28, 2019)
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criteria provided, single submitter
Method: clinical testing
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Hypogonadotropic hypogonadism 7 with or without anosmia
Affected status: unknown
Allele origin:
unknown
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Mendelics
Accession: SCV001136742.1
First in ClinVar: Jan 09, 2020 Last updated: Jan 09, 2020 |
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Uncertain significance
(Dec 15, 2017)
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criteria provided, single submitter
Method: clinical testing
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Hypogonadotropic hypogonadism 7 with or without anosmia
Affected status: unknown
Allele origin:
germline
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Illumina Laboratory Services, Illumina
Accession: SCV001314288.1
First in ClinVar: May 31, 2020 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. However, the evidence from the literature, in combination with allele frequency data from public databases where available, was not sufficient to rule this variant in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance. (less)
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Uncertain significance
(Jan 07, 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: SCV002070007.1
First in ClinVar: Jan 29, 2022 Last updated: Jan 29, 2022 |
Comment:
DNA sequence analysis of the GNRHR gene demonstrated a sequence change, c.436C>T, in exon 1 that results in an amino acid change, p.Pro146Ser. This sequence … (more)
DNA sequence analysis of the GNRHR gene demonstrated a sequence change, c.436C>T, in exon 1 that results in an amino acid change, p.Pro146Ser. This sequence change has been described in the gnomAD database with a population frequency of 0.38% in Latino subpopulations and it has been observed in one individual in the homozygous state (dbSNP rs144900788). This sequence change was identified in the heterozygous state in individuals with normosmic idiopathic hypogonadotropic hypogonadism and Kallmann syndrome but a second pathogenic change in this gene was not identified (PMID: 22745237 and PMID: 16359986). The p.Pro146Ser change affects a highly conserved amino acid residue located in a domain of the GNRHR protein that is known to be functional. The p.Pro146Ser substitution appears to be deleterious using several in-silico pathogenicity prediction tools (SIFT, PolyPhen2, Align GVGD, REVEL). Due to these contrasting evidences and the lack of functional studies, the clinical significance of the p.Pro146Ser change remains unknown at this time. (less)
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Likely benign
(Jan 18, 2024)
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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: SCV001029546.5
First in ClinVar: Dec 17, 2019 Last updated: Feb 20, 2024 |
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Uncertain significance
(Feb 27, 2024)
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criteria provided, single submitter
Method: clinical testing
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GNRHR-related condition
Affected status: unknown
Allele origin:
germline
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PreventionGenetics, part of Exact Sciences
Accession: SCV004754554.1
First in ClinVar: Mar 16, 2024 Last updated: Mar 16, 2024 |
Comment:
The GNRHR c.436C>T variant is predicted to result in the amino acid substitution p.Pro146Ser. This variant has been reported in the heterozygous state in several … (more)
The GNRHR c.436C>T variant is predicted to result in the amino acid substitution p.Pro146Ser. This variant has been reported in the heterozygous state in several patients with hypogonadotropic hypogonadism/Kallmann syndrome (see, for example, Vagenakis et al. 2005. PubMed ID: 16359986; Gianetti et al. 2012. PubMed ID: 22745237; Miraoui et al. 2013. PubMed ID: 23643382, Table S3; Stamou et al. 2019. PubMed ID: 30921766), delayed puberty (Saengkaew et al. 2021. PubMed ID: 34403359), or a suspected disorder of sex development (Zidoune et al. 2022. PubMed ID: 36110220, supplementary data). However, a second pathogenic variant was not identified in these patients. In addition, no genetic or functional study has been performed to assess the pathogenicity of this variant. This variant has been observed with an allele frequency of up to ~0.38% in Latino individuals from a large population database, including 1 homozygote. At this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence. (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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Isolated GNRH deficiency: genotypic and phenotypic characteristics of the genetically heterogeneous Greek population. | Stamou MI | European journal of endocrinology | 2017 | PMID: 27884859 |
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 |
When genetic load does not correlate with phenotypic spectrum: lessons from the GnRH receptor (GNRHR). | Gianetti E | The Journal of clinical endocrinology and metabolism | 2012 | PMID: 22745237 |
Congenital hypogonadotropic hypogonadism due to GnRH receptor mutations in three brothers reveal sites affecting conformation and coupling. | Tello JA | PloS one | 2012 | PMID: 22679506 |
G protein-coupled receptors involved in GnRH regulation: molecular insights from human disease. | Noel SD | Molecular and cellular endocrinology | 2011 | PMID: 21736917 |
GnRH receptor mutations in isolated gonadotropic deficiency. | Chevrier L | Molecular and cellular endocrinology | 2011 | PMID: 21645587 |
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 |
Genotype and phenotype of patients with gonadotropin-releasing hormone receptor mutations. | Kim HG | Frontiers of hormone research | 2010 | PMID: 20389088 |
The gonadotropin-releasing hormone (GnRH)-1 gene, the GnRH receptor gene, and their promoters in patients with idiopathic hypogonadotropic hypogonadism with or without resistance to GnRH action. | Vagenakis GA | Fertility and sterility | 2005 | PMID: 16359986 |
Text-mined citations for rs144900788 ...
HelpRecord last updated Mar 17, 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.