ClinVar Genomic variation as it relates to human health
NM_000406.3(GNRHR):c.785G>A (p.Arg262Gln)
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.785G>A (p.Arg262Gln)
Variation ID: 16024 Accession: VCV000016024.26
- Type and length
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single nucleotide variant, 1 bp
- Location
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Cytogenetic: 4q13.2 4: 67740682 (GRCh38) [ NCBI UCSC ] 4: 68606400 (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 Jul 7, 2024 Oct 15, 2023 - HGVS
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Nucleotide Protein Molecular
consequenceNM_000406.3:c.785G>A MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_000397.1:p.Arg262Gln missense NM_001012763.2:c.657G>A NP_001012781.1:p.Thr219= synonymous NC_000004.12:g.67740682C>T NC_000004.11:g.68606400C>T NG_009293.1:g.20405G>A P30968:p.Arg262Gln - Protein change
- R262Q
- Other names
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- Canonical SPDI
- NC_000004.12:67740681: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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0.00060 (T)
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Allele frequency
Help
The frequency of the allele represented by this VCV record.
1000 Genomes Project 30x 0.00047
1000 Genomes Project 0.00060
Trans-Omics for Precision Medicine (TOPMed) 0.00107
The Genome Aggregation Database (gnomAD) 0.00132
The Genome Aggregation Database (gnomAD), exomes 0.00179
Exome Aggregation Consortium (ExAC) 0.00203
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 |
185 | 213 |
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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Pathogenic/Likely pathogenic (9) |
criteria provided, multiple submitters, no conflicts
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Mar 2, 2023 | RCV000030908.42 | |
Pathogenic (2) |
criteria provided, multiple submitters, no conflicts
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Oct 15, 2023 | RCV000494391.10 | |
Uncertain significance (1) |
no assertion criteria provided
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Mar 8, 2021 | RCV001849268.1 | |
See cases
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Likely pathogenic (1) |
criteria provided, single submitter
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Feb 22, 2017 | RCV004584328.1 |
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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Pathogenic
(Jun 20, 2019)
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criteria provided, single submitter
Method: clinical testing
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Hypogonadotropic hypogonadism 7 without anosmia
Affected status: yes
Allele origin:
germline
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Hadassah Hebrew University Medical Center
Accession: SCV001437669.1
First in ClinVar: Oct 10, 2020 Last updated: Oct 10, 2020 |
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Likely pathogenic
(Jul 26, 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: yes
Allele origin:
germline
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MGZ Medical Genetics Center
Accession: SCV002579437.1
First in ClinVar: Oct 15, 2022 Last updated: Oct 15, 2022
Comment:
ACMG criteria applied: PM3_STR, PS3_MOD, PM2_SUP, PP3
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Number of individuals with the variant: 1
Sex: female
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Pathogenic
(Oct 15, 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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Labcorp Genetics (formerly Invitae), Labcorp
Accession: SCV002209386.3
First in ClinVar: Mar 28, 2022 Last updated: Feb 20, 2024 |
Comment:
This sequence change replaces arginine, which is basic and polar, with glutamine, which is neutral and polar, at codon 262 of the GNRHR protein (p.Arg262Gln). … (more)
This sequence change replaces arginine, which is basic and polar, with glutamine, which is neutral and polar, at codon 262 of the GNRHR protein (p.Arg262Gln). This variant is present in population databases (rs104893837, gnomAD 0.5%), and has an allele count higher than expected for a pathogenic variant. This missense change has been observed in individual(s) with isolated hypogonadotropic hypogonadism (PMID: 9371856, 9425890, 10022417, 10084584, 16968799, 26207952). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 16024). 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. Experimental studies have shown that this missense change affects GNRHR function (PMID: 9371856, 9425890, 12574221). For these reasons, this variant has been classified as Pathogenic. (less)
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Pathogenic
(Sep 19, 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:
germline
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Illumina Laboratory Services, Illumina
Accession: SCV000916073.1
First in ClinVar: May 27, 2019 Last updated: May 27, 2019 |
Comment:
The GNRHR c.785G>A (p.Arg262Gln) missense variant has been reported in at least seven studies and is found in at least 18 individuals with isolated GnRH … (more)
The GNRHR c.785G>A (p.Arg262Gln) missense variant has been reported in at least seven studies and is found in at least 18 individuals with isolated GnRH deficiency, including in five in a homozygous state, including one sibling pair, in ten in a compound heterozygous state, including four sibling pairs, and in four in a heterozygous state (de Roux et al. 1997; Lin et al. 2006; Laitinen et al. 2012; Gianetti et al. 2012; Tommiska et al. 2014; Hietamaki et al. 2017; Goncalves et al. 2017). Probands exhibited idiopathic hypogonadotropic hypogonadism, delayed puberty, incomplete puberty, or isolated hypogonadotropic hypogonadism. Control data are unavailable for this variant, which is reported at a frequency of 0.005313 in the European (Finnish) population of the Genome Aggregation Database. Functional evaluation of receptor stimulation by ligand induced signaling stimulation of p.Arg262Gln variant GnRHR resulted in significantly less phospholipase C activity compared to wild type GnRHR, demonstrating p.Arg262Gln is functionally deficient (Bedecarrats et al. 2003). Based on the evidence, the p.Arg262Gln 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
(-)
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criteria provided, single submitter
Method: research
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Hypogonadotropic hypogonadism 7 with or without anosmia
Affected status: no
Allele origin:
germline
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UNC Molecular Genetics Laboratory, University of North Carolina at Chapel Hill
Study: NSIGHT-NC NEXUS
Accession: SCV001251526.1 First in ClinVar: May 31, 2020 Last updated: May 31, 2020
Comment:
carrier finding
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Comment:
The GNRHR c.785G>A (p.R262Q) variant has been reported in the compound heterozygous state in at at least 4 families with idiopathic hypogonadotropic hypogonadism (PMID: 9371856; … (more)
The GNRHR c.785G>A (p.R262Q) variant has been reported in the compound heterozygous state in at at least 4 families with idiopathic hypogonadotropic hypogonadism (PMID: 9371856; 10084584; 9425890; 10690855). (less)
Number of individuals with the variant: 1
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Pathogenic
(May 06, 2021)
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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: unknown
Allele origin:
germline
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Victorian Clinical Genetics Services, Murdoch Childrens Research Institute
Additional submitter:
Shariant Australia, Australian Genomics
Accession: SCV002767943.1
First in ClinVar: Dec 24, 2022 Last updated: Dec 24, 2022 |
Comment:
Based on the classification scheme VCGS_Germline_v1.3.4, this variant is classified as Pathogenic. Following criteria are met: 0102 - Loss of function is a known mechanism … (more)
Based on the classification scheme VCGS_Germline_v1.3.4, this variant is classified as Pathogenic. Following criteria are met: 0102 - Loss of function is a known mechanism of disease in this gene and is associated with hypogonadotropic hypogonadism 7 without anosmia (MIM#146110). (I) 0106 - This gene is associated with autosomal recessive disease. (I) 0200 - Variant is predicted to result in a missense amino acid change from arginine to glutamine. (I) 0251 - This variant is heterozygous. (I) 0304 - Variant is present in gnomAD (v2) <0.01 for a recessive condition (503 heterozygotes, 1 homozygote). (SP) 0309 - An alternative amino acid change at the same position has been observed in gnomAD (v2) (5 heterozygotes, 0 homozygotes). (I) 0502 - Missense variant with conflicting in silico predictions and uninformative conservation. (I) 0600 - Variant is located in the annotated third intracellular loop (PMID: 9371856, 16968799). (I) 0705 - No comparable missense variants have previous evidence for pathogenicity. (I) 0801 - This variant has strong previous evidence of pathogenicity in unrelated individuals. This is one of the most frequently reported variants in this gene and has been reported in numerous patients with hypogonadotropic hypogonadism, in both the homozygous or compound heterozygous states (ClinVar, PMID: 9371856, 9425890, 16968799, 22724017, 29182666, 28611058). (SP) 1002 - This variant has moderate functional evidence supporting abnormal protein function. Functional studies on this variant showed a decrease in phospholipase C activity compared to wild type, resulting in a partial loss of function (PMID: 9371856, 12574221). (SP) 1208 - Inheritance information for this variant is not currently available in this individual. (I) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign (less)
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Pathogenic
(Apr 25, 2022)
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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: SCV002800265.1
First in ClinVar: Dec 31, 2022 Last updated: Dec 31, 2022 |
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Pathogenic
(Feb 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: SCV000583021.6
First in ClinVar: Jul 02, 2017 Last updated: Mar 04, 2023 |
Comment:
Published functional studies demonstrate a damaging effect on IP3 production and GnRH signal transmission (de Roux et al., 1997; Layman et al., 1998); In silico … (more)
Published functional studies demonstrate a damaging effect on IP3 production and GnRH signal transmission (de Roux et al., 1997; Layman et al., 1998); 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: 9371856, 24732674, 16968799, 22745237, 26207952, 23643382, 22788855, 15728205, 12364481, 19820032, 12574221, 17235395, 23155690, 9425890, 21247312, 20696889, 27884859, 26572316, 17074994, 27899157, 12477532, 29419413, 28611058, 29182666, 30476149, 31200363, 31980526, 32870266, 34198905, 34426522, 10690855, 31589614, 11384641) (less)
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Pathogenic
(Mar 02, 2023)
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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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Revvity Omics, Revvity
Accession: SCV002024894.3
First in ClinVar: Nov 29, 2021 Last updated: Feb 04, 2024 |
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Likely pathogenic
(Feb 22, 2017)
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criteria provided, single submitter
Method: clinical testing
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see cases
Affected status: yes
Allele origin:
unknown
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Institute of Human Genetics, University Hospital Muenster
Accession: SCV002577771.2
First in ClinVar: Oct 08, 2022 Last updated: Jul 07, 2024 |
Comment:
ACMG categories: PM1,PP2,PP3,PP4,PP5,BP1
Number of individuals with the variant: 1
Clinical Features:
Hypogonadotropic hypogonadism (present)
Age: 20-29 years
Sex: male
Tissue: blood
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Pathogenic
(Dec 01, 2006)
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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: SCV000037671.3
First in ClinVar: Apr 04, 2013 Last updated: Aug 22, 2016 |
Comment on evidence:
For discussion of the arg262-to-gln (R262Q) mutation in the GNRHR gene that was found in compound heterozygous state in patients with hypogonadotropic hypogonadism (HH7; 146110) … (more)
For discussion of the arg262-to-gln (R262Q) mutation in the GNRHR gene that was found in compound heterozygous state in patients with hypogonadotropic hypogonadism (HH7; 146110) by de Roux et al. (1997) and Seminara et al. (2000), see 138850.0001. The R262Q mutation in GNRHR was also found in compound heterozygous state in 4 sibs with HH by Layman et al. (1998) (see 138850.0003) and in 3 sibs with HH by Caron et al. (1999) (see 138850.0004). De Roux et al. (1999) found the R262Q mutation in compound heterozygous state in 3 sibs with HH, who carried both the Q106R (138850.0001) and S217R (138850.0005) mutations on the other allele. In 2 brothers with HH7, Lin et al. (2006) identified homozygosity for the R262Q mutation in the GNRHR gene. The proband, who presented at 15 years of age with delayed puberty, responded to a short course of testosterone with appropriate progress through puberty, whereas his younger brother showed little response after treatment. Lin et al. (2006) concluded that homozygous partial loss-of-function mutations in GNRHR, such as R262Q, can cause variable phenotypes, including apparent delayed puberty. (less)
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Pathogenic
(Jan 06, 2020)
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no assertion criteria provided
Method: curation
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Hypogonadotropic hypogonadism 7 with or without anosmia
Affected status: unknown
Allele origin:
germline
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Reproductive Health Research and Development, BGI Genomics
Accession: SCV001142337.1
First in ClinVar: Jan 13, 2020 Last updated: Jan 13, 2020 |
Comment:
NM_000406.2:c.785G>A in the GNRHR gene has an allele frequency of 0.005 in European (Finnish) subpopulation in the gnomAD database. The GNRHR c.785G>A (p.Arg262Gln) missense variant … (more)
NM_000406.2:c.785G>A in the GNRHR gene has an allele frequency of 0.005 in European (Finnish) subpopulation in the gnomAD database. The GNRHR c.785G>A (p.Arg262Gln) missense variant has been reported in multiple individuals with isolated GnRH deficiency, including homozygous Arg262Gln and compound heterozygous Gln106Arg/Phe309del; c.[785G>A];[937_947del]; Q106R/R262Q; L166P/R262Q; R139H/R262Q and R262Q/del309F (PMID: 22724017; 22745237; 29182666; 28611058). Functional evaluation of receptor stimulation by ligand induced signaling stimulation of p.Arg262Gln variant GnRHR resulted in significantly less phospholipase C activity compared to wild type GnRHR, demonstrating p.Arg262Gln is functionally deficient (PMID: 12574221). Taken together, we interprete this variant as Pathogenic/Likely pathogenic variant. ACMG/AMP Criteria applied: PM3_VeryStrong, PS3, PP4. (less)
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Uncertain significance
(Mar 08, 2021)
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no assertion criteria provided
Method: literature only
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Amenorrhea
Affected status: yes
Allele origin:
unknown
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Yale Center for Mendelian Genomics, Yale University
Study: Yale Center for Mendelian Genomics
Accession: SCV002106765.1 First in ClinVar: Mar 28, 2022 Last updated: Mar 28, 2022 |
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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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Parental exome analysis identifies shared carrier status for a second recessive disorder in couples with an affected child. | Mor-Shaked H | European journal of human genetics : EJHG | 2021 | PMID: 33223529 |
Increased Burden of Rare Sequence Variants in GnRH-Associated Genes in Women With Hypothalamic Amenorrhea. | Delaney A | The Journal of clinical endocrinology and metabolism | 2021 | PMID: 32870266 |
GnRH receptor gene mutations in adolescents and young adults presenting with signs of partial gonadotropin deficiency. | Hietamäki J | PloS one | 2017 | PMID: 29182666 |
GNRHR biallelic and digenic mutations in patients with normosmic congenital hypogonadotropic hypogonadism. | Gonçalves CI | Endocrine connections | 2017 | PMID: 28611058 |
Expanding the Spectrum of Founder Mutations Causing Isolated Gonadotropin-Releasing Hormone Deficiency. | Choi JH | The Journal of clinical endocrinology and metabolism | 2015 | PMID: 26207952 |
Genetics of congenital hypogonadotropic hypogonadism in Denmark. | Tommiska J | European journal of medical genetics | 2014 | PMID: 24732674 |
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 |
A homozygous R262Q mutation in the gonadotropin-releasing hormone receptor presenting as constitutional delay of growth and puberty with subsequent borderline oligospermia. | Lin L | The Journal of clinical endocrinology and metabolism | 2006 | PMID: 16968799 |
Two common naturally occurring mutations in the human gonadotropin-releasing hormone (GnRH) receptor have differential effects on gonadotropin gene expression and on GnRH-mediated signal transduction. | Bedecarrats GY | The Journal of clinical endocrinology and metabolism | 2003 | PMID: 12574221 |
Successful use of pulsatile gonadotropin-releasing hormone (GnRH) for ovulation induction and pregnancy in a patient with GnRH receptor mutations. | Seminara SB | The Journal of clinical endocrinology and metabolism | 2000 | PMID: 10690855 |
Resistance of hypogonadic patients with mutated GnRH receptor genes to pulsatile GnRH administration. | Caron P | The Journal of clinical endocrinology and metabolism | 1999 | PMID: 10084584 |
The same molecular defects of the gonadotropin-releasing hormone receptor determine a variable degree of hypogonadism in affected kindred. | de Roux N | The Journal of clinical endocrinology and metabolism | 1999 | PMID: 10022417 |
Mutations in gonadotropin-releasing hormone receptor gene cause hypogonadotropic hypogonadism. | Layman LC | Nature genetics | 1998 | PMID: 9425890 |
A family with hypogonadotropic hypogonadism and mutations in the gonadotropin-releasing hormone receptor. | de Roux N | The New England journal of medicine | 1997 | PMID: 9371856 |
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Text-mined citations for rs104893837 ...
HelpRecord last updated Oct 13, 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.