ClinVar Genomic variation as it relates to human health
NM_000406.3(GNRHR):c.416G>A (p.Arg139His)
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.
No data submitted for somatic clinical impact
No data submitted for oncogenicity
Variant Details
- Identifiers
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NM_000406.3(GNRHR):c.416G>A (p.Arg139His)
Variation ID: 16030 Accession: VCV000016030.34
- Type and length
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single nucleotide variant, 1 bp
- Location
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Cytogenetic: 4q13.2 4: 67753920 (GRCh38) [ NCBI UCSC ] 4: 68619638 (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 Aug 22, 2016 Apr 15, 2024 Dec 18, 2023 - HGVS
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Nucleotide Protein Molecular
consequenceNM_000406.3:c.416G>A MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_000397.1:p.Arg139His missense NM_001012763.2:c.416G>A NP_001012781.1:p.Arg139His missense NC_000004.12:g.67753920C>T NC_000004.11:g.68619638C>T NG_009293.1:g.7167G>A P30968:p.Arg139His - Protein change
- R139H
- Other names
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- Canonical SPDI
- NC_000004.12:67753919:C:T
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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.
The Genome Aggregation Database (gnomAD), exomes 0.00014
Trans-Omics for Precision Medicine (TOPMed) 0.00014
Exome Aggregation Consortium (ExAC) 0.00017
The Genome Aggregation Database (gnomAD) 0.00021
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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GNRHR | - | - |
GRCh38 GRCh37 |
175 | 203 |
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
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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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Pathogenic (5) |
criteria provided, multiple submitters, no conflicts
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Mar 1, 2023 | RCV000030914.40 | |
Pathogenic (4) |
criteria provided, multiple submitters, no conflicts
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Dec 18, 2023 | RCV000497820.25 |
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
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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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Pathogenic
(Sep 14, 2016)
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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: SCV000450929.3
First in ClinVar: Dec 06, 2016 Last updated: May 24, 2019 |
Comment:
The GNRHR c.416G>A (p.Arg139His) missense variant has been identified in a homozygous state in ten individuals and in a compound heterozygous state in at least … (more)
The GNRHR c.416G>A (p.Arg139His) missense variant has been identified in a homozygous state in ten individuals and in a compound heterozygous state in at least 11 individuals with isolated gonadotropin-releasing hormone (GnRH) deficiency, and in a heterozygous state in five unaffected family members (Costa et al. 2001; Wolczynski et al. 2003; Laitinen et al. 2012; Gianetti et al. 2012; Hero et al. 2012; Gurbuz et al. 2012; Choi et al. 2015). The p.Arg139His variant was absent from 422 controls and is reported at a frequency of 0.00076 in the European (Finnish) population of the Exome Aggregation Consortium. Functional studies in COS-7 cells demonstrated normal localization of the mutant protein at the cell surface but complete elimination of GnRH-binding activity and activation of intracellular transduction pathways (Costa et al. 2001; Leanos-Miranda et al. 2002). Based on the evidence, the p.Arg139His variant is classified as pathogenic for isolated GnRH deficiency. This variant was observed by ICSL as part of a predisposition screen in an ostensibly healthy population. (less)
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Pathogenic
(Apr 11, 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: SCV000589592.6
First in ClinVar: Aug 20, 2017 Last updated: Mar 04, 2023 |
Comment:
In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 12364481, … (more)
In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 12364481, 11397871, 26207952, 22745237, 32763379, 31589614, 26044071, 12667096, 23155690, 21645587, 34426522, 20207726, 16213849, 24117998, 21736917, 22766261, 25016926, 20389088, 14689055, 22405597, 21717411, 31200363, 30476149, 32222824, 27544332, 34198905) (less)
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Pathogenic
(Aug 01, 2021)
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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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CeGaT Center for Human Genetics Tuebingen
Accession: SCV001961834.14
First in ClinVar: Oct 08, 2021 Last updated: Apr 15, 2024 |
Number of individuals with the variant: 1
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Pathogenic
(Mar 23, 2020)
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criteria provided, single submitter
Method: clinical testing
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Hypogonadotropic hypogonadism 7 with or without anosmia
Affected status: yes
Allele origin:
unknown
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Centre for Mendelian Genomics, University Medical Centre Ljubljana
Accession: SCV001367651.2
First in ClinVar: Jul 05, 2020 Last updated: Dec 12, 2020 |
Comment:
This variant was classified as: Pathogenic. The following ACMG criteria were applied in classifying this variant: PS3,PS4_MOD,PM2,PM3,PP2,PP3,PP4.
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Pathogenic
(Nov 16, 2021)
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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: SCV002783899.1
First in ClinVar: Dec 31, 2022 Last updated: Dec 31, 2022 |
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Pathogenic
(Mar 01, 2023)
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criteria provided, single submitter
Method: clinical testing
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Hypogonadotropic hypogonadism 7 with or without anosmia
(Autosomal recessive inheritance)
Affected status: yes
Allele origin:
germline
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Neuberg Centre For Genomic Medicine, NCGM
Accession: SCV004176413.1
First in ClinVar: Dec 17, 2023 Last updated: Dec 17, 2023 |
Clinical Features:
Abnormality of the genital system (present)
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Pathogenic
(Dec 18, 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: SCV001590395.4
First in ClinVar: May 10, 2021 Last updated: Feb 14, 2024 |
Comment:
This sequence change replaces arginine, which is basic and polar, with histidine, which is basic and polar, at codon 139 of the GNRHR protein (p.Arg139His). … (more)
This sequence change replaces arginine, which is basic and polar, with histidine, which is basic and polar, at codon 139 of the GNRHR protein (p.Arg139His). This variant is present in population databases (rs104893842, gnomAD 0.05%). This missense change has been observed in individuals with hypogonadotropic hypogonadism (PMID: 11397871, 22724017, 25016926, 26207952, 27544332). It is commonly reported in individuals of Brazilian ancestry (PMID: 11397871, 22724017, 25016926, 26207952, 27544332). ClinVar contains an entry for this variant (Variation ID: 16030). 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 GNRHR protein function with a positive predictive value of 80%. Experimental studies have shown that this missense change affects GNRHR function (PMID: 11397871, 12364481). For these reasons, this variant has been classified as Pathogenic. (less)
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Pathogenic
(Jun 01, 2001)
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no assertion criteria provided
Method: literature only
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HYPOGONADOTROPIC HYPOGONADISM 7 WITHOUT ANOSMIA
Affected status: not provided
Allele origin:
germline
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OMIM
Accession: SCV000037677.3
First in ClinVar: Apr 04, 2013 Last updated: Aug 22, 2016 |
Comment on evidence:
In a Brazilian woman with complete hypogonadotropic hypogonadism (HH7; 146110), Costa et al. (2001) identified homozygosity for an arg139-to-his (R139H) substitution located in the conserved … (more)
In a Brazilian woman with complete hypogonadotropic hypogonadism (HH7; 146110), Costa et al. (2001) identified homozygosity for an arg139-to-his (R139H) substitution located in the conserved DRS motif at the junction of the third transmembrane and the second intracellular loop of the GNRHR gene. The R139H mutation completely eliminated detectable GNRH-binding activity and prevented GNRH-induced stimulation of inositol phosphate accumulation in vitro. The patient had undetectable serum basal LH and FSH levels that failed to respond to GNRH stimulation. (less)
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Pathogenic
(Dec 19, 2022)
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no assertion criteria provided
Method: clinical testing
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not provided
Affected status: yes
Allele origin:
germline
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Genetic Services Laboratory, University of Chicago
Accession: SCV003839564.1
First in ClinVar: Mar 18, 2023 Last updated: Mar 18, 2023 |
Comment:
DNA sequence analysis of the GNRHR gene demonstrated a sequence change, c.416G>A , in exon 1 that results in an amino acid change, p.Arg139His. The … (more)
DNA sequence analysis of the GNRHR gene demonstrated a sequence change, c.416G>A , in exon 1 that results in an amino acid change, p.Arg139His. The p.Arg139His change affects a highly conserved amino acid residue located in a domain of the GNRHR protein that is known to be functional. The p.Arg139His substitution appears to be deleterious using several in-silico pathogenicity prediction tools (SIFT, PolyPhen2, Align GVGD, REVEL). This pathogenic sequence change has previously been described in individuals with hypogonadotropic hypogonadism and is commonly reported in individuals of Brazilian ancestry (PMID: 11397871, 22724017, 25016926, 26207952, 27544332). This sequence change has been described in the gnomAD database with a frequency of 0.055% in the European subpopulation (dbSNP rs104893842). These collective evidences indicate that this sequence change is pathogenic. (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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Mutations in gonadotropin-releasing hormone signaling pathway in two nIHH patients with successful pregnancy outcomes. | Zernov N | Reproductive biology and endocrinology : RB&E | 2016 | PMID: 27544332 |
Expanding the Spectrum of Founder Mutations Causing Isolated Gonadotropin-Releasing Hormone Deficiency. | Choi JH | The Journal of clinical endocrinology and metabolism | 2015 | PMID: 26207952 |
Role of gonadotropin-releasing hormone receptor mutations in patients with a wide spectrum of pubertal delay. | Beneduzzi D | Fertility and sterility | 2014 | PMID: 25016926 |
Distribution of gene mutations associated with familial normosmic idiopathic hypogonadotropic hypogonadism. | Gürbüz F | Journal of clinical research in pediatric endocrinology | 2012 | PMID: 22766261 |
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 |
Reversible congenital hypogonadotropic hypogonadism in patients with CHD7, FGFR1 or GNRHR mutations. | Laitinen EM | PloS one | 2012 | PMID: 22724017 |
Circulating antimüllerian hormone levels in boys decline during early puberty and correlate with inhibin B. | Hero M | Fertility and sterility | 2012 | PMID: 22405597 |
Receptor-misrouting: an unexpectedly prevalent and rescuable etiology in gonadotropin-releasing hormone receptor-mediated hypogonadotropic hypogonadism. | Leaños-Miranda A | The Journal of clinical endocrinology and metabolism | 2002 | PMID: 12364481 |
Two novel mutations in the gonadotropin-releasing hormone receptor gene in Brazilian patients with hypogonadotropic hypogonadism and normal olfaction. | Costa EM | The Journal of clinical endocrinology and metabolism | 2001 | PMID: 11397871 |
Text-mined citations for rs104893842 ...
HelpRecord last updated Apr 15, 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.