VCV000016023.73 - ClinVar

NM_000406.3(GNRHR):c.317A>G (p.Gln106Arg)

Germline

Classification

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.

(26)

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/Likely pathogenic

criteria provided, multiple submitters, no conflicts

Somatic

No data submitted for somatic clinical impact

Somatic

No data submitted for oncogenicity

Variant Details

Identifiers

NM_000406.3(GNRHR):c.317A>G (p.Gln106Arg)

Variation ID: 16023 Accession: VCV000016023.73

Type and length

single nucleotide variant, 1 bp

Location

Cytogenetic: 4q13.2 4: 67754019 (GRCh38) [ NCBI UCSC ] 4: 68619737 (GRCh37) [ NCBI UCSC ]

Timeline in ClinVar

	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	Nov 24, 2024	Oct 9, 2024

HGVS

Nucleotide	Protein	Molecular consequence
NM_000406.3:c.317A>G MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.	NP_000397.1:p.Gln106Arg	missense
NM_001012763.2:c.317A>G	NP_001012781.1:p.Gln106Arg	missense
NC_000004.12:g.67754019T>C
NC_000004.11:g.68619737T>C
NG_009293.1:g.7068A>G
	P30968:p.Gln106Arg

... more HGVS ... less HGVS

Protein change

Q106R

Other names

Canonical SPDI

NC_000004.12:67754018:T:C

Functional consequence Help The effect of the variant on RNA or protein function, based on experimental evidence from submitters.

Global minor allele frequency (GMAF) Help The 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.

0.00120 (C)

Allele frequency Help The frequency of the allele represented by this VCV record.

1000 Genomes Project 30x 0.00094

1000 Genomes Project 0.00120

The Genome Aggregation Database (gnomAD) 0.00234

Trans-Omics for Precision Medicine (TOPMed) 0.00238

Exome Aggregation Consortium (ExAC) 0.00252

The Genome Aggregation Database (gnomAD), exomes 0.00284

Links

ClinGen: CA130197 UniProtKB: P30968#VAR_019313 OMIM: 138850.0001 dbSNP: rs104893836 VarSome

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
Gene	OMIM	HI score Help 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.
GNRHR		-	-	GRCh38 GRCh37	186	214

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.
Hypogonadotropic hypogonadism 7 with or without anosmia	Pathogenic/Likely pathogenic (11)	criteria provided, multiple submitters, no conflicts	Oct 9, 2024	RCV000190591.34
not provided	Pathogenic (9)	criteria provided, multiple submitters, no conflicts	Jan 21, 2024	RCV000255385.46
Isolated congenital hypogonadotropic hypogonadism	Pathogenic (1)	criteria provided, single submitter	Mar 27, 2024	RCV000599632.7
Gonadotropin deficiency	Pathogenic (1)	criteria provided, single submitter	Mar 5, 2018	RCV000662016.6
Infertility disorder	Pathogenic (1)	no assertion criteria provided	-	RCV001327939.3
Hypogonadotropic hypogonadism	not provided (1)	no classification provided	-	RCV003330392.1
GNRHR-related disorder	Pathogenic (1)	no assertion criteria provided	Jun 3, 2024	RCV003415714.6
Inborn genetic diseases	Pathogenic (1)	criteria provided, single submitter	Mar 14, 2024	RCV004018637.2

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.
Likely pathogenic (Jun 20, 2019)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Hypogonadotropic hypogonadism 7 without anosmia Affected status: yes Allele origin: germline	Hadassah Hebrew University Medical Center Accession: SCV001430595.1 First in ClinVar: Aug 24, 2020 Last updated: Aug 24, 2020	Publications: PubMed (1) PubMed: 33223529
Pathogenic (Nov 15, 2021)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	not provided Affected status: yes Allele origin: germline	Seattle Children's Hospital Molecular Genetics Laboratory, Seattle Children's Hospital Accession: SCV002525663.1 First in ClinVar: Jun 11, 2022 Last updated: Jun 11, 2022	Comment: The GNRHR p.Gln106Arg variant is known to cause partial loss-of-function of the GnRH receptor is the most common disease causing variant in the GNRHR gene … (more) The GNRHR p.Gln106Arg variant is known to cause partial loss-of-function of the GnRH receptor is the most common disease causing variant in the GNRHR gene and has been observed primarily in a homozygous state in individuals with IGD without anosmia (PMID: 22745237, PMID: 9371856 and others). While variants in GNRHR are typically homozygous or compound heterozygous, the p.Gln106Arg variant has been observed as a heterozygous change in individuals with Kallmann syndrome, normosmic idiopathic hypogonadotropic hypogonadism (nIHH), and adult-onset idiopathic hypogonadotropic hypogonadism (AOIHH) (PMID: 22745237, PMID: 20696). Individuals who are heterozygous for the p.Gln106Arg variant may also be asymptomatic carriers with normal puberty. This variant is present in the gnomAD database (allele frequency = 0.00275, gnomAD v2.1.1), but the prevalence of heterozygous GNRHR variants has been shown to be significantly higher among affected individuals compared to controls (PMID: 22745237). (less) Clinical Features: Perineal hypospadias (present)
Pathogenic (Nov 15, 2022)	criteria provided, single submitter (Athena Diagnostics Criteria) Method: clinical testing	not provided Affected status: unknown Allele origin: unknown	Athena Diagnostics Accession: SCV004229679.1 First in ClinVar: Jan 26, 2024 Last updated: Jan 26, 2024	Publications: PubMed (17) PubMed: 33223529‚ 30476149‚ 26207952‚ 25016926‚ 22745237‚ 10999776‚ 11397842‚ 11397871‚ 12364481‚ 12574221‚ 15728205‚ 17235395‚ 21292259‚ 21664240‚ 23155690‚ 9371856‚ 33968656 Comment: The frequency of this variant in the general population is consistent with pathogenicity (http://gnomad.broadinstitute.org). This variant segregates with disease in multiple families. Assessment of experimental … (more) The frequency of this variant in the general population is consistent with pathogenicity (http://gnomad.broadinstitute.org). This variant segregates with disease in multiple families. Assessment of experimental evidence suggests this variant results in abnormal protein function. (PMID: 9371856, 12364481, 12574221) In multiple individuals, this variant has been seen with a single recessive pathogenic variant in the same gene, suggesting this variant may also be pathogenic. (less)
Pathogenic (Jan 21, 2024)	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015)) Method: clinical testing	not provided Affected status: unknown Allele origin: germline	Labcorp Genetics (formerly Invitae), Labcorp Accession: SCV000931625.5 First in ClinVar: Aug 14, 2019 Last updated: Feb 20, 2024	Publications: PubMed (12) PubMed: 9371856‚ 10999776‚ 11397871‚ 12057744‚ 20696889‚ 22745237‚ 23155690‚ 23643382‚ 26207952‚ 12364481‚ 12574221‚ 15728205 Comment: This sequence change replaces glutamine, which is neutral and polar, with arginine, which is basic and polar, at codon 106 of the GNRHR protein (p.Gln106Arg). … (more) This sequence change replaces glutamine, which is neutral and polar, with arginine, which is basic and polar, at codon 106 of the GNRHR protein (p.Gln106Arg). This variant is present in population databases (rs104893836, gnomAD 0.6%), and has an allele count higher than expected for a pathogenic variant. This missense change has been observed in individual(s) with varying degrees of HH or Kallman syndrome and hypogonadotropic hypogonadism (HH) (PMID: 9371856, 10999776, 11397871, 12057744, 20696889, 22745237, 23155690, 23643382, 26207952). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 16023). 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 not expected to disrupt GNRHR protein function with a negative predictive value of 80%. Experimental studies have shown that this missense change affects GNRHR function (PMID: 9371856, 12364481, 12574221, 15728205). For these reasons, this variant has been classified as Pathogenic. (less)
Pathogenic (Oct 09, 2024)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Hypogonadotropic hypogonadism 7 with or without anosmia (Autosomal recessive inheritance) Affected status: unknown Allele origin: germline	Victorian Clinical Genetics Services, Murdoch Childrens Research Institute Additional submitter: Shariant Australia, Australian Genomics Accession: SCV002557930.4 First in ClinVar: Aug 08, 2022 Last updated: Nov 24, 2024	Publications: PubMed (10) PubMed: 9371856‚ 12057744‚ 15728205‚ 20389088‚ 22745237‚ 23650335‚ 25016926‚ 26207952‚ 29182666‚ 30476149 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 for this gene and is associated with hypogonadotropic hypogonadism 7 without anosmia (MIM#146110). (I) 0106 - This gene is known to be associated with autosomal recessive disease. (I) 0200 - Variant is predicted to result in a missense amino acid change from glutamine to arginine (I). 0251 - This variant is heterozygous. (I) 0304 - Variant is present in gnomAD (v2) <0.01 for recessive indication (773 heterozygotes, 2 homozygotes). Sub-population: European, non-Finnish (517 heterozygotes, 1 homozygote). (SP) 0502 - Missense variant with conflicting in silico predictions and uninformative conservation. Minor amino acid change, very high conservation. (I) 0600 - Variant is located in the annotated domain, seven-transmembrane G protein-coupled receptor superfamily, extracellular loop (DECIPHER, NCBI). (I) 0705 - No comparable variants have previous evidence for pathogenicity. (I) 0801 - This variant has very strong previous evidence of pathogenicity in unrelated individuals. There are multiple reports of homozygous and compound heterozygous individuals with hypogonadotropic hypogonadism (PMIDs: 9371856, 12057744, 20389088, 22745237, 25016926, 26207952, 29182666, ClinVar, HGMD). It has been reported to be the most frequent variant causing hypogonadotropic hypogonadism, and also considered a founder variant in Europeans, African-American and South Asian populations (PMID: 26207952). There have also been several reports of heterozygous patients, with the possibility of environmental factors contributing to the phenotype (PMIDs: 22745237, 23650335). (SP) 0902 - This variant has moderate evidence for segregation with disease (PMIDs: 9371856, 30476149). (SP) 1002 - This variant has moderate functional evidence supporting abnormal protein function. In vitro studies showed decreased binding to its ligand, GNRH (PMID: 9371856, 15728205). (SP) 1201 - Heterozygous variant detected in trans with a second pathogenic heterozygous variant (c.806C>T, p.(Thr269Met)) in a recessive disease. (I) 1205 - This variant has been shown to be paternally inherited. (I) (less)
Pathogenic (Sep 20, 2018)	criteria provided, single submitter (ICSL Variant Classification Criteria 09 May 2019) Method: clinical testing	Hypogonadotropic hypogonadism 7 with or without anosmia Affected status: unknown Allele origin: germline	Illumina Laboratory Services, Illumina Accession: SCV000916074.1 First in ClinVar: May 27, 2019 Last updated: May 27, 2019	Publications: PubMed (8) PubMed: 17235395‚ 11397842‚ 15728205‚ 12574221‚ 22745237‚ 10999776‚ 12057744‚ 9371856 Comment: The GNRHR c.317A>G (p.Gln106Arg) missense variant has been reported in at least six studies and is found in a total of 32 individuals with isolated … (more) The GNRHR c.317A>G (p.Gln106Arg) missense variant has been reported in at least six studies and is found in a total of 32 individuals with isolated GnRH deficiency, including in four in a homozygous state, in 15 in a compound heterozygous state, and in 13 in a heterozygous state (de Roux 1997; Kottler et al. 2000; Pitteloud et al. 2001; Dewailly et al. 2002; Pitteloud et al. 2007; Gianetti et al. 2012). The affected individuals exhibited a range of phenotypes from mild to severe, with homozygotes exhibiting a milder phenotype than compound heterozygotes (Pitteloud et al. 2001; Dewailly et al. 2002; Bedecarrats et al. 2003). The p.Gln106Arg variant was also found in eight unaffected relatives (Pitteloud et al. 2001; Dewailly et al. 2002). The p.Gln106Arg variant was reported in two chromosomes of 604 control chromosomes and is reported at a frequency of 0.006015 in the Ashkenazi Jewish population of the Genome Aggregation Database. Two homozygous individuals are found in the Genome Aggregation Consortium, though these may be explained by homozygotes presenting a mild phenotype (Dewailly et al. 2002; Bedecarrats et al. 2003). In vitro expression analysis in CHO-K1 and COS-7 cells found p.Gln106Arg to have significantly reduced GNRH binding activity and reduced inositol phosphates binding compared to wildtype (de Roux 1997, Kottler et al. 2000; LeaÃ±os-Miranda et al. 2005). Based on the collective evidence, the p.Gln106Arg 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)
Pathogenic (May 31, 2019)	criteria provided, single submitter (Classification criteria August 2017) Method: clinical testing	Hypogonadotropic hypogonadism 7 with or without anosmia (Autosomal recessive inheritance) Affected status: yes Allele origin: germline	Institute of Human Genetics Munich, Klinikum Rechts Der Isar, TU München Accession: SCV001150121.1 First in ClinVar: Feb 03, 2020 Last updated: Feb 03, 2020	Sex: male Tissue: blood
Pathogenic (Apr 02, 2019)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Hypogonadotropic hypogonadism 7 with or without anosmia Affected status: yes Allele origin: germline	Institute of Human Genetics, University of Leipzig Medical Center Accession: SCV001428658.1 First in ClinVar: Aug 17, 2020 Last updated: Aug 17, 2020	Number of individuals with the variant: 1
Pathogenic (Jan 14, 2022)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	not provided Affected status: yes Allele origin: germline	Genetic Services Laboratory, University of Chicago Accession: SCV002070515.1 First in ClinVar: Jan 29, 2022 Last updated: Jan 29, 2022	Comment: The p.Gln106Arg change affects a highly conserved amino acid residue located in a domain of the GNRHR protein that is known to be functional. The … (more) The p.Gln106Arg change affects a highly conserved amino acid residue located in a domain of the GNRHR protein that is known to be functional. The p.Gln106Arg substitution appears to be deleterious using several in-silico pathogenicity prediction tools (SIFT, PolyPhen2, Align GVGD, REVEL). This sequence change has been described in the gnomAD database with a population frequency of 0.40% in the non-Finnish European subpopulation (dbSNP rs104893836) and it is considered one of the most commonly observed pathogenic sequence change in this gene (PMID: 20389088). This sequence change has been reported to in individuals and families with hypogonadotropic hypogonadism (HH) (PMID: 9371856, 12057744, 11397871, 10999776) and has also been reported in several individuals Kallman syndrome (PMID: 20696889, 23155690, 23643382, 26207952, 22745237). In-vitro studies showed the binding of GnRH was reduced in cells transfected with the p.Gln106Arg sequence change (PMID: 9371856). (less)
Pathogenic (Dec 19, 2016)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Hypogonadotropic hypogonadism 7 with or without anosmia Affected status: yes Allele origin: germline	Institute of Human Genetics, University Hospital Muenster Accession: SCV002496155.1 First in ClinVar: Apr 08, 2022 Last updated: Apr 08, 2022	Comment: ACMG categories: PS1,PS5,BP1 Number of individuals with the variant: 1 Clinical Features: Hypogonadotropic hypogonadism (present) Age: 20-29 years Sex: female Tissue: blood
Pathogenic (Mar 05, 2018)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Hypogonadotropic hypogonadism Affected status: no Allele origin: inherited	Genomic Research Center, Shahid Beheshti University of Medical Sciences Accession: SCV000784348.2 First in ClinVar: Jul 13, 2018 Last updated: Dec 11, 2022	Number of individuals with the variant: 1 Age: 20-29 years Sex: female Geographic origin: Iran
Pathogenic (Apr 11, 2022)	criteria provided, single submitter (GeneDx Variant Classification Process June 2021) Method: clinical testing	Not Provided Affected status: yes Allele origin: germline	GeneDx Accession: SCV000321746.12 First in ClinVar: Oct 09, 2016 Last updated: Mar 04, 2023	Comment: Published functional studies demonstrate a damaging effect by reducing the binding of GnRH-A and decreasing the activation of phospholipase C (de Roux et al., 1997); … (more) Published functional studies demonstrate a damaging effect by reducing the binding of GnRH-A and decreasing the activation of phospholipase C (de Roux et al., 1997); 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, 25077900, 15728205, 22745237, 12574221, 26572316, 29431110, 28754744, 34426522, 31589614, 12679486, 23155690, 19820032, 10999776, 20696889, 23643382, 17235395, 9371856, 20389088, 10690855, 11397842, 10022417, 28348023, 26792935, 12057744, 29419413, 11397871, 28611058, 29182666, 30609409, 31980526, 30476149, 32870266, 19449676, 31200363, 34055685, 31130284, 34198905, 26207952) (less)
Pathogenic (May 24, 2023)	criteria provided, single submitter (LabCorp Variant Classification Summary - May 2015) Method: clinical testing	Hypogonadotropic hypogonadism 7 with or without anosmia Affected status: unknown Allele origin: germline	Women's Health and Genetics/Laboratory Corporation of America, LabCorp Accession: SCV003934500.1 First in ClinVar: Jun 24, 2023 Last updated: Jun 24, 2023	Publications: PubMed (3) PubMed: 25077900‚ 12364481‚ 9371856 Comment: Variant summary: GNRHR c.317A>G (p.Gln106Arg) results in a conservative amino acid change located in the GPCR, rhodopsin-like, 7TM domain (IPR017452) of the encoded protein sequence. … (more) Variant summary: GNRHR c.317A>G (p.Gln106Arg) results in a conservative amino acid change located in the GPCR, rhodopsin-like, 7TM domain (IPR017452) of the encoded protein sequence. Three of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 0.0028 in 251236 control chromosomes in the gnomAD database, including 1 homozygotes. c.317A>G has been reported in the literature in multiple bi-allelic and heterozygous individuals affected Kallmann syndrome and hypogonadotropic hypogonadism (Marcos_2014). This variant also segregated in a family affected with idiopathic hypogonadotropic hypogonadism (de Roux_1997). Multiple publications have reported experimental evidence that this variant reduced ligand binding (examples: de Roux_1997 and Leanos-Miranda_2002). The following publications have been ascertained in the context of this evaluation (PMID: 12364481, 9371856, 25077900). Fourteen clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 and all classified the variant as pathogenic/likely pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic. (less)
Pathogenic (Jun 02, 2023)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Hypogonadotropic hypogonadism 7 with or without anosmia Affected status: unknown Allele origin: germline	Revvity Omics, Revvity Accession: SCV002024891.3 First in ClinVar: Nov 29, 2021 Last updated: Feb 04, 2024
Likely pathogenic (Mar 29, 2024)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Hypogonadotropic hypogonadism 7 with or without anosmia Affected status: unknown Allele origin: germline	Center for Genomic Medicine, King Faisal Specialist Hospital and Research Center Accession: SCV004807813.1 First in ClinVar: Apr 06, 2024 Last updated: Apr 06, 2024
Pathogenic (Mar 27, 2024)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Isolated congenital hypogonadotropic hypogonadism (Autosomal recessive inheritance) Affected status: unknown Allele origin: germline	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine Accession: SCV000245617.3 First in ClinVar: Sep 14, 2015 Last updated: Apr 20, 2024	Publications: PubMed (7) PubMed: 12364481‚ 9371856‚ 20389088‚ 22745237‚ 21645587‚ 26207952‚ 23643382 Comment: The p.Gln106Arg variant in GNRHR is an established pathogenic variant for hypogonadotropic hypogonadism (HH) and is the most common disease-causing HH variant in GNRHR (Kim … (more) The p.Gln106Arg variant in GNRHR is an established pathogenic variant for hypogonadotropic hypogonadism (HH) and is the most common disease-causing HH variant in GNRHR (Kim 2010 PMID: 20389088). This variant has been identified in the homozygous and compound heterozygous state in multiple individuals with HH and segregated with disease in multiple affected relatives from multiple families. In addition, there are few reports of heterozygote carriers of the p.Gln106Arg variant presenting with isolated hypogonadotropic hypogonadism (Chevrier 2011 PMID: 21645587, Gianetti 2012 PMID: 22745237); however, it is unclear at this time if carrier status for this variant is associated with an increased risk for development of HH. This variant has been reported by other clinical laboratories in ClinVar (Variation ID: 16023) and has also been identified in 0.6% (185/29604) of Ashkenazi Jewish chromosomes including 10 total homozygotes by gnomAD (http://gnomad.broadinstitute.org, v.4.0.0). Although this variant has been seen in the general population, its frequency is low enough to be consistent with a recessive carrier frequency. In vitro functional assays indicate this variant leads to partial loss of GNRHR function (de Roux 1997 PMID: 9371856, Leanos-Miranda 2002 PMID: 12364481), correlating with the relatively milder phenotype observed in individuals who are homozygous for this variant. In summary, this variant meets criteria to be classified as pathogenic for autosomal recessive hypogonadotropic hypogonadism. ACMG/AMP Criteria applied: PM3_Very Strong, PP1_Strong, PM3. (less)
Pathogenic (Mar 14, 2024)	criteria provided, single submitter (Ambry Variant Classification Scheme 2023) Method: clinical testing	Inborn genetic diseases Affected status: unknown Allele origin: germline	Ambry Genetics Accession: SCV004878661.1 First in ClinVar: May 01, 2024 Last updated: May 01, 2024	Publications: PubMed (17) PubMed: 9371856‚ 11397842‚ 12057744‚ 12364481‚ 12574221‚ 12679486‚ 15728205‚ 20389088‚ 20696889‚ 22745237‚ 23643382‚ 25016926‚ 25077900‚ 26792935‚ 28348023‚ 34403359‚ 36407308 Comment: The c.317A>G (p.Q106R) alteration is located in exon 1 (coding exon 1) of the GNRHR gene. This alteration results from an A to G substitution … (more) The c.317A>G (p.Q106R) alteration is located in exon 1 (coding exon 1) of the GNRHR gene. This alteration results from an A to G substitution at nucleotide position 317, causing the glutamine (Q) at amino acid position 106 to be replaced by an arginine (R). Based on data from gnomAD, the G allele has an overall frequency of 0.275% (777/282638) total alleles studied. The highest observed frequency was 0.598% (62/10362) of Ashkenazi Jewish alleles. This variant has been identified in the homozygous state and in trans with another GNRHR variant in numerous individuals with features consistent with hypogonadotropic hypogonadism and has been reported to segregate with disease in several families (Dwyer, 2022; Saengkaew, 2021; Caburet, 2017; Marcos, 2014; Beneduzzi, 2014; Sykiotis, 2010; Karges, 2003; Dewailly, 2002; Pitteloud, 2001; de Roux, 1997). This amino acid position is highly conserved in available vertebrate species. In multiple assays testing GNRHR function, this variant has been shown to significantly reduce GnRH binding and decrease PLC activity as measured by decrease in intracellular IP production in response to GnRH (de Roux, 1997; Leanos-Miranda, 2005; Bedecarrats, 2003; Leanos-Miranda, 2002). This alteration is predicted to be deleterious by in silico analysis. Based on the available evidence, this alteration is classified as pathogenic. (less)
Pathogenic (Apr 04, 2023)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	not provided Affected status: yes Allele origin: germline	Clinical Genetics Laboratory, Skane University Hospital Lund Accession: SCV005198409.1 First in ClinVar: Aug 25, 2024 Last updated: Aug 25, 2024
Pathogenic (Apr 01, 2023)	criteria provided, single submitter (CeGaT Center For Human Genetics Tuebingen Variant Classification Criteria Version 2) Method: clinical testing	not provided Affected status: yes Allele origin: germline	CeGaT Center for Human Genetics Tuebingen Accession: SCV000693150.30 First in ClinVar: Dec 06, 2016 Last updated: Oct 20, 2024	Comment: GNRHR: PM3:Very Strong, PP1:Moderate, PS3:Moderate, PM2:Supporting, BP4 Number of individuals with the variant: 4
Pathogenic (-)	no assertion criteria provided Method: clinical testing	not provided Affected status: yes Allele origin: germline	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center Additional submitter: Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen Study: VKGL Data-share Consensus Accession: SCV001968940.1 First in ClinVar: Oct 08, 2021 Last updated: Oct 08, 2021
Pathogenic (Feb 01, 2007)	no assertion criteria provided Method: literature only	HYPOGONADOTROPIC HYPOGONADISM 7 WITHOUT ANOSMIA Affected status: not provided Allele origin: germline	OMIM Accession: SCV000037669.4 First in ClinVar: Apr 04, 2013 Last updated: Feb 26, 2022	Publications: PubMed (8) PubMed: 9371856‚ 10022417‚ 10690855‚ 17235395‚ 7557974‚ 11397842‚ 11397871‚ 12679486 Comment on evidence: In a sister and brother with hypogonadotropic hypogonadism (HH7; 146110), de Roux et al. (1997) identified compound heterozygosity for a 317G-A transition in the GNRHR … (more) In a sister and brother with hypogonadotropic hypogonadism (HH7; 146110), de Roux et al. (1997) identified compound heterozygosity for a 317G-A transition in the GNRHR gene, resulting in a gln106-to-arg (Q106R) substitution, and a 785G-A transition, resulting in an arg262-to-gln (R262Q; 138850.0002) substitution. Both residues are highly conserved and are located in the first extracellular and third intracellular loop of the GNRH receptor, respectively. The unaffected parents and sister, who were clinically and endocrinologically normal, were each heterozygous for 1 of the mutations. Functional analysis demonstrated that GNRH binding was markedly reduced, but not eliminated, with the Q106R mutant, whereas GNRH binding was similar to wildtype with the R262Q mutant. In a brother and 2 sisters with HH, de Roux et al. (1999) identified compound heterozygosity for the Q106R and R262Q mutations in the GNRHR gene; in addition, all 3 sibs carried another GNRHR missense mutation (S217R; 138850.0005) on the same allele with Q106R. In 2 sisters with primary amenorrhea and no breast development at 25 and 18 years of age, respectively, Seminara et al. (2000) identified compound heterozygosity for the Q106R and R262Q mutations in the GNRHR gene. The apparently unaffected parents were heterozygous for the mutations. Pitteloud et al. (2007) reexamined this family and identified heterozygosity for an additional missense mutation in the FGFR1 gene (136350.0016) in the 2 sisters and in their father, who had a history of delayed puberty. Mutation analysis of the children of the younger sister revealed that her unaffected daughter, who underwent normal puberty, was heterozygous for the mutation in FGFR1 but had no mutations in the GNRHR gene, and that her prepubertal 10-year-old twin sons, born without cryptorchidism or microphallus, were each heterozygous for 1 of the mutations in the GNRHR gene but did not have any mutations in the FGFR1 gene. Pitteloud et al. (2007) concluded that defects in 2 different genes can synergize to produce a more severe phenotype in families with hypogonadotropic hypogonadism than either alone, and that this digenic model may account for some of the phenotypic heterogeneity seen in GnRH deficiency. In a woman with complete HH, Kottler et al. (2000) identified compound heterozygosity for Q106R and a nonsense mutation in the GNRHR gene (L314X; 138850.0007). In a 26-year-old male with mild HH, who had hypogonadal testosterone levels, detectable but apulsatile gonadotropin secretion, and normal testicular size, and who developed sperm after treatment with CG (see 118860), Pitteloud et al. (2001) identified homozygosity for the Q106R mutation in the GNRHR gene. The authors noted that de Roux et al. (1997) had previously shown that GNRH binding is decreased, but not eliminated, with the Q106R mutant. In 4 Brazilian sibs with partial HH, Costa et al. (2001) identified compound heterozygosity for Q106R and another missense mutation in the GNRHR gene (N10K; 138850.0009). In 2 brothers with severe HH, Karges et al. (2003) identified compound heterozygosity for Q106R and another missense mutation in the GNRHR gene (A171T; 138850.0012). (less)
Pathogenic (Jun 03, 2024)	no assertion criteria provided Method: clinical testing	GNRHR-related condition Affected status: unknown Allele origin: germline	PreventionGenetics, part of Exact Sciences Accession: SCV004107189.3 First in ClinVar: Nov 20, 2023 Last updated: Oct 08, 2024	Comment: The GNRHR c.317A>G variant is predicted to result in the amino acid substitution p.Gln106Arg. This variant has been documented as causative for hypogonadotropic hypogonadism when … (more) The GNRHR c.317A>G variant is predicted to result in the amino acid substitution p.Gln106Arg. This variant has been documented as causative for hypogonadotropic hypogonadism when present in the homozygous state or the compound heterozygous state with another pathogenic GNRHR variant (de Roux et al. 1997. PubMed ID: 9371856; Choi et al. 2005. PubMed ID: 26207952; Gianetti et al. 2012. PubMed ID: 22745237; Miraoui et al. 2013. PubMed ID: 23643382). This variant has also been detected in the heterozygous state in one man with hypogonadotropic hypogonadism (Table 2. Dwyer et al. 2023. PubMed ID: 36268624). In vitro functional studies have shown the p.Gln106Arg variant results in partial loss of function of the GNRHR receptor protein (de Roux et al. 1997. PubMed ID: 9371856; Leanos-Miranda et al. 2002. PubMed ID: 12364481; Gianetti et al. 2012. PubMed ID: 22745237). This variant is reported in 0.60% of alleles in individuals of Ashkenazi Jewish descent in gnomAD. This variant is interpreted as pathogenic. (less)
Pathogenic (Jan 06, 2020)	no assertion criteria provided Method: curation	Hypogonadotropic hypogonadism 7 with or without anosmia Affected status: unknown Allele origin: germline	Reproductive Health Research and Development, BGI Genomics Accession: SCV001142338.1 First in ClinVar: Jan 13, 2020 Last updated: Jan 13, 2020	Comment: NM_000406.2:c.317A>G in the GNRHR gene has an allele frequency of 0.006 in Ashkenazi Jewish subpopulation in the gnomAD database. The c.317A>G(p.Q106R) variant in the GNRHR … (more) NM_000406.2:c.317A>G in the GNRHR gene has an allele frequency of 0.006 in Ashkenazi Jewish subpopulation in the gnomAD database. The c.317A>G(p.Q106R) variant in the GNRHR gene has been reported previously in the compound heterozygous (Q106R/R262Q; P96S/Q106R; Q106R/S217R) and homozygous states in association with hypogonadotropic hypogonadism (PMID: 9371856; 22745237; 23643382). In vitro functional studies demonstrated that p.Q106R results in a loss of function of the receptor protein (PMID: 9371856). Taken together, we interprete this variant as Pathogenic/Likely pathogenic variant. ACMG/AMP Criteria applied: PS3; PM3_Strong; PP4. (less)
Pathogenic (-)	no assertion criteria provided Method: provider interpretation	Infertility disorder Affected status: yes Allele origin: germline	MAGI's Lab - Research, MAGI Group Accession: SCV001432717.1 First in ClinVar: Mar 22, 2021 Last updated: Mar 22, 2021	Observation 1: Observation 2:
Pathogenic (-)	no assertion criteria provided Method: clinical testing	not provided Affected status: yes Allele origin: germline	Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen Study: VKGL Data-share Consensus Accession: SCV001741838.3 First in ClinVar: Jul 07, 2021 Last updated: Sep 08, 2021
not provided (-)	no classification provided Method: phenotyping only	Hypogonadotropic hypogonadism Affected status: unknown Allele origin: paternal	GenomeConnect - Invitae Patient Insights Network Accession: SCV004037563.1 First in ClinVar: Oct 07, 2023 Last updated: Oct 07, 2023	Comment: Variant classified as Pathogenic and reported on 01-08-2018 by Invitae. These coordinates are approximate and are based on NGS. GenomeConnect-Invitae Patient Insights Network assertions are … (more) Variant classified as Pathogenic and reported on 01-08-2018 by Invitae. These coordinates are approximate and are based on NGS. GenomeConnect-Invitae Patient Insights Network assertions are reported exactly as they appear on the patient-provided report from the testing laboratory. Registry team members make no attempt to reinterpret the clinical significance of the variant. Phenotypic details are available under supporting information. (less) Clinical Features: Abnormality of vision (present) , Myopia (present) , Vertigo (present) , Hyperacusis (present) , Abnormal oral cavity morphology (present) , Atrophic scars (present) , Hyperextensible … (more) Abnormality of vision (present) , Myopia (present) , Vertigo (present) , Hyperacusis (present) , Abnormal oral cavity morphology (present) , Atrophic scars (present) , Hyperextensible skin (present) , Hyperpigmentation of the skin (present) , Thickened skin (present) , Abnormality of the cardiovascular system (present) , Bleeding with minor or no trauma (present) , Bruising susceptibility (present) , Abnormal erythrocyte morphology (present) , Autoimmunity (present) , Abnormal inflammatory response (present) , Decreased response to growth hormone stimulation test (present) , Obesity (present) , Abnormal muscle physiology (present) , Abnormality of the musculature of the limbs (present) , Abnormal morphology of the pelvis musculature (present) , Diabetes insipidus (present) , Hyperthyroidism (present) , Abnormality of the parathyroid physiology (present) , Abnormality of the bladder (present) , Abnormality of urine homeostasis (present) , Cognitive impairment (present) , Abnormality of coordination (present) , Memory impairment (present) , Movement disorder (present) , Anxiety (present) , Depression (present) , Abnormal delivery (present) , Pregnancy history (present) , Abnormal placenta morphology (present) (less) Indication for testing: Diagnostic Age: 40-49 years Sex: female Method: Exome Sequencing Testing laboratory: Invitae Date variant was reported to submitter: 2018-01-08 Testing laboratory interpretation: Pathogenic
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Comment:

The GNRHR p.Gln106Arg variant is known to cause partial loss-of-function of the GnRH receptor is the most common disease causing variant in the GNRHR gene and has been observed primarily in a homozygous state in individuals with IGD without anosmia (PMID: 22745237, PMID: 9371856 and others). While variants in GNRHR are typically homozygous or compound heterozygous, the p.Gln106Arg variant has been observed as a heterozygous change in individuals with Kallmann syndrome, normosmic idiopathic hypogonadotropic hypogonadism (nIHH), and adult-onset idiopathic hypogonadotropic hypogonadism (AOIHH) (PMID: 22745237, PMID: 20696). Individuals who are heterozygous for the p.Gln106Arg variant may also be asymptomatic carriers with normal puberty. This variant is present in the gnomAD database (allele frequency = 0.00275, gnomAD v2.1.1), but the prevalence of heterozygous GNRHR variants has been shown to be significantly higher among affected individuals compared to controls (PMID: 22745237).

Comment:

The frequency of this variant in the general population is consistent with pathogenicity (http://gnomad.broadinstitute.org). This variant segregates with disease in multiple families. Assessment of experimental evidence suggests this variant results in abnormal protein function. (PMID: 9371856, 12364481, 12574221) In multiple individuals, this variant has been seen with a single recessive pathogenic variant in the same gene, suggesting this variant may also be pathogenic.

Comment:

This sequence change replaces glutamine, which is neutral and polar, with arginine, which is basic and polar, at codon 106 of the GNRHR protein (p.Gln106Arg). This variant is present in population databases (rs104893836, gnomAD 0.6%), and has an allele count higher than expected for a pathogenic variant. This missense change has been observed in individual(s) with varying degrees of HH or Kallman syndrome and hypogonadotropic hypogonadism (HH) (PMID: 9371856, 10999776, 11397871, 12057744, 20696889, 22745237, 23155690, 23643382, 26207952). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 16023). 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 not expected to disrupt GNRHR protein function with a negative predictive value of 80%. Experimental studies have shown that this missense change affects GNRHR function (PMID: 9371856, 12364481, 12574221, 15728205). For these reasons, this variant has been classified as Pathogenic.

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 of disease for this gene and is associated with hypogonadotropic hypogonadism 7 without anosmia (MIM#146110). (I) 0106 - This gene is known to be associated with autosomal recessive disease. (I) 0200 - Variant is predicted to result in a missense amino acid change from glutamine to arginine (I). 0251 - This variant is heterozygous. (I) 0304 - Variant is present in gnomAD (v2) <0.01 for recessive indication (773 heterozygotes, 2 homozygotes). Sub-population: European, non-Finnish (517 heterozygotes, 1 homozygote). (SP) 0502 - Missense variant with conflicting in silico predictions and uninformative conservation. Minor amino acid change, very high conservation. (I) 0600 - Variant is located in the annotated domain, seven-transmembrane G protein-coupled receptor superfamily, extracellular loop (DECIPHER, NCBI). (I) 0705 - No comparable variants have previous evidence for pathogenicity. (I) 0801 - This variant has very strong previous evidence of pathogenicity in unrelated individuals. There are multiple reports of homozygous and compound heterozygous individuals with hypogonadotropic hypogonadism (PMIDs: 9371856, 12057744, 20389088, 22745237, 25016926, 26207952, 29182666, ClinVar, HGMD). It has been reported to be the most frequent variant causing hypogonadotropic hypogonadism, and also considered a founder variant in Europeans, African-American and South Asian populations (PMID: 26207952). There have also been several reports of heterozygous patients, with the possibility of environmental factors contributing to the phenotype (PMIDs: 22745237, 23650335). (SP) 0902 - This variant has moderate evidence for segregation with disease (PMIDs: 9371856, 30476149). (SP) 1002 - This variant has moderate functional evidence supporting abnormal protein function. In vitro studies showed decreased binding to its ligand, GNRH (PMID: 9371856, 15728205). (SP) 1201 - Heterozygous variant detected in trans with a second pathogenic heterozygous variant (c.806C>T, p.(Thr269Met)) in a recessive disease. (I) 1205 - This variant has been shown to be paternally inherited. (I)

Comment:

The GNRHR c.317A>G (p.Gln106Arg) missense variant has been reported in at least six studies and is found in a total of 32 individuals with isolated GnRH deficiency, including in four in a homozygous state, in 15 in a compound heterozygous state, and in 13 in a heterozygous state (de Roux 1997; Kottler et al. 2000; Pitteloud et al. 2001; Dewailly et al. 2002; Pitteloud et al. 2007; Gianetti et al. 2012). The affected individuals exhibited a range of phenotypes from mild to severe, with homozygotes exhibiting a milder phenotype than compound heterozygotes (Pitteloud et al. 2001; Dewailly et al. 2002; Bedecarrats et al. 2003). The p.Gln106Arg variant was also found in eight unaffected relatives (Pitteloud et al. 2001; Dewailly et al. 2002). The p.Gln106Arg variant was reported in two chromosomes of 604 control chromosomes and is reported at a frequency of 0.006015 in the Ashkenazi Jewish population of the Genome Aggregation Database. Two homozygous individuals are found in the Genome Aggregation Consortium, though these may be explained by homozygotes presenting a mild phenotype (Dewailly et al. 2002; Bedecarrats et al. 2003). In vitro expression analysis in CHO-K1 and COS-7 cells found p.Gln106Arg to have significantly reduced GNRH binding activity and reduced inositol phosphates binding compared to wildtype (de Roux 1997, Kottler et al. 2000; LeaÃ±os-Miranda et al. 2005). Based on the collective evidence, the p.Gln106Arg 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.

Comment:

The p.Gln106Arg change affects a highly conserved amino acid residue located in a domain of the GNRHR protein that is known to be functional. The p.Gln106Arg substitution appears to be deleterious using several in-silico pathogenicity prediction tools (SIFT, PolyPhen2, Align GVGD, REVEL). This sequence change has been described in the gnomAD database with a population frequency of 0.40% in the non-Finnish European subpopulation (dbSNP rs104893836) and it is considered one of the most commonly observed pathogenic sequence change in this gene (PMID: 20389088). This sequence change has been reported to in individuals and families with hypogonadotropic hypogonadism (HH) (PMID: 9371856, 12057744, 11397871, 10999776) and has also been reported in several individuals Kallman syndrome (PMID: 20696889, 23155690, 23643382, 26207952, 22745237). In-vitro studies showed the binding of GnRH was reduced in cells transfected with the p.Gln106Arg sequence change (PMID: 9371856).

Comment:

Published functional studies demonstrate a damaging effect by reducing the binding of GnRH-A and decreasing the activation of phospholipase C (de Roux et al., 1997); 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, 25077900, 15728205, 22745237, 12574221, 26572316, 29431110, 28754744, 34426522, 31589614, 12679486, 23155690, 19820032, 10999776, 20696889, 23643382, 17235395, 9371856, 20389088, 10690855, 11397842, 10022417, 28348023, 26792935, 12057744, 29419413, 11397871, 28611058, 29182666, 30609409, 31980526, 30476149, 32870266, 19449676, 31200363, 34055685, 31130284, 34198905, 26207952)

Comment:

Variant summary: GNRHR c.317A>G (p.Gln106Arg) results in a conservative amino acid change located in the GPCR, rhodopsin-like, 7TM domain (IPR017452) of the encoded protein sequence. Three of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 0.0028 in 251236 control chromosomes in the gnomAD database, including 1 homozygotes. c.317A>G has been reported in the literature in multiple bi-allelic and heterozygous individuals affected Kallmann syndrome and hypogonadotropic hypogonadism (Marcos_2014). This variant also segregated in a family affected with idiopathic hypogonadotropic hypogonadism (de Roux_1997). Multiple publications have reported experimental evidence that this variant reduced ligand binding (examples: de Roux_1997 and Leanos-Miranda_2002). The following publications have been ascertained in the context of this evaluation (PMID: 12364481, 9371856, 25077900). Fourteen clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 and all classified the variant as pathogenic/likely pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic.

Comment:

The p.Gln106Arg variant in GNRHR is an established pathogenic variant for hypogonadotropic hypogonadism (HH) and is the most common disease-causing HH variant in GNRHR (Kim 2010 PMID: 20389088). This variant has been identified in the homozygous and compound heterozygous state in multiple individuals with HH and segregated with disease in multiple affected relatives from multiple families. In addition, there are few reports of heterozygote carriers of the p.Gln106Arg variant presenting with isolated hypogonadotropic hypogonadism (Chevrier 2011 PMID: 21645587, Gianetti 2012 PMID: 22745237); however, it is unclear at this time if carrier status for this variant is associated with an increased risk for development of HH. This variant has been reported by other clinical laboratories in ClinVar (Variation ID: 16023) and has also been identified in 0.6% (185/29604) of Ashkenazi Jewish chromosomes including 10 total homozygotes by gnomAD (http://gnomad.broadinstitute.org, v.4.0.0). Although this variant has been seen in the general population, its frequency is low enough to be consistent with a recessive carrier frequency. In vitro functional assays indicate this variant leads to partial loss of GNRHR function (de Roux 1997 PMID: 9371856, Leanos-Miranda 2002 PMID: 12364481), correlating with the relatively milder phenotype observed in individuals who are homozygous for this variant. In summary, this variant meets criteria to be classified as pathogenic for autosomal recessive hypogonadotropic hypogonadism. ACMG/AMP Criteria applied: PM3_Very Strong, PP1_Strong, PM3.

Comment:

The c.317A>G (p.Q106R) alteration is located in exon 1 (coding exon 1) of the GNRHR gene. This alteration results from an A to G substitution at nucleotide position 317, causing the glutamine (Q) at amino acid position 106 to be replaced by an arginine (R). Based on data from gnomAD, the G allele has an overall frequency of 0.275% (777/282638) total alleles studied. The highest observed frequency was 0.598% (62/10362) of Ashkenazi Jewish alleles. This variant has been identified in the homozygous state and in trans with another GNRHR variant in numerous individuals with features consistent with hypogonadotropic hypogonadism and has been reported to segregate with disease in several families (Dwyer, 2022; Saengkaew, 2021; Caburet, 2017; Marcos, 2014; Beneduzzi, 2014; Sykiotis, 2010; Karges, 2003; Dewailly, 2002; Pitteloud, 2001; de Roux, 1997). This amino acid position is highly conserved in available vertebrate species. In multiple assays testing GNRHR function, this variant has been shown to significantly reduce GnRH binding and decrease PLC activity as measured by decrease in intracellular IP production in response to GnRH (de Roux, 1997; Leanos-Miranda, 2005; Bedecarrats, 2003; Leanos-Miranda, 2002). This alteration is predicted to be deleterious by in silico analysis. Based on the available evidence, this alteration is classified as pathogenic.

Comment:

The GNRHR c.317A>G variant is predicted to result in the amino acid substitution p.Gln106Arg. This variant has been documented as causative for hypogonadotropic hypogonadism when present in the homozygous state or the compound heterozygous state with another pathogenic GNRHR variant (de Roux et al. 1997. PubMed ID: 9371856; Choi et al. 2005. PubMed ID: 26207952; Gianetti et al. 2012. PubMed ID: 22745237; Miraoui et al. 2013. PubMed ID: 23643382). This variant has also been detected in the heterozygous state in one man with hypogonadotropic hypogonadism (Table 2. Dwyer et al. 2023. PubMed ID: 36268624). In vitro functional studies have shown the p.Gln106Arg variant results in partial loss of function of the GNRHR receptor protein (de Roux et al. 1997. PubMed ID: 9371856; Leanos-Miranda et al. 2002. PubMed ID: 12364481; Gianetti et al. 2012. PubMed ID: 22745237). This variant is reported in 0.60% of alleles in individuals of Ashkenazi Jewish descent in gnomAD. This variant is interpreted as pathogenic.

Comment:

NM_000406.2:c.317A>G in the GNRHR gene has an allele frequency of 0.006 in Ashkenazi Jewish subpopulation in the gnomAD database. The c.317A>G(p.Q106R) variant in the GNRHR gene has been reported previously in the compound heterozygous (Q106R/R262Q; P96S/Q106R; Q106R/S217R) and homozygous states in association with hypogonadotropic hypogonadism (PMID: 9371856; 22745237; 23643382). In vitro functional studies demonstrated that p.Q106R results in a loss of function of the receptor protein (PMID: 9371856). Taken together, we interprete this variant as Pathogenic/Likely pathogenic variant. ACMG/AMP Criteria applied: PS3; PM3_Strong; PP4.

Comment:

Variant classified as Pathogenic and reported on 01-08-2018 by Invitae. These coordinates are approximate and are based on NGS. GenomeConnect-Invitae Patient Insights Network assertions are reported exactly as they appear on the patient-provided report from the testing laboratory. Registry team members make no attempt to reinterpret the clinical significance of the variant. Phenotypic details are available under supporting information.

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.

Comment:

Citations for germline classification of this variant

Title	Author	Journal	Year	Link
Reversible hypogonadotropic hypogonadism in men with the fertile eunuch/Pasqualini syndrome: A single-center natural history study.	Dwyer AA	Frontiers in endocrinology	2022	PMID: 36407308
Genetic evaluation supports differential diagnosis in adolescent patients with delayed puberty.	Saengkaew T	European journal of endocrinology	2021	PMID: 34403359
A partial loss-of-function variant in GNRNR gene in a Chinese cohort with idiopathic hypogonadotropic hypogonadism.	Chen Y	Translational andrology and urology	2021	PMID: 33968656
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
Similarities and differences in the reproductive phenotypes of women with congenital hypogonadotrophic hypogonadism caused by GNRHR mutations and women with polycystic ovary syndrome.	Maione L	Human reproduction (Oxford, England)	2019	PMID: 30476149
GnRH receptor gene mutations in adolescents and young adults presenting with signs of partial gonadotropin deficiency.	Hietamäki J	PloS one	2017	PMID: 29182666
A homozygous mutation of GNRHR in a familial case diagnosed with polycystic ovary syndrome.	Caburet S	European journal of endocrinology	2017	PMID: 28348023
MANAGEMENT OF ENDOCRINE DISEASE: Reversible hypogonadotropic hypogonadism.	Dwyer AA	European journal of endocrinology	2016	PMID: 26792935
Expanding the Spectrum of Founder Mutations Causing Isolated Gonadotropin-Releasing Hormone Deficiency.	Choi JH	The Journal of clinical endocrinology and metabolism	2015	PMID: 26207952
The prevalence of CHD7 missense versus truncating mutations is higher in patients with Kallmann syndrome than in typical CHARGE patients.	Marcos S	The Journal of clinical endocrinology and metabolism	2014	PMID: 25077900
Role of gonadotropin-releasing hormone receptor mutations in patients with a wide spectrum of pubertal delay.	Beneduzzi D	Fertility and sterility	2014	PMID: 25016926
Approach to the patient with hypogonadotropic hypogonadism.	Silveira LF	The Journal of clinical endocrinology and metabolism	2013	PMID: 23650335
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
Molecular defects of the GnRH-receptor gene in Chinese patients with idiopathic hypogonadotropic hypogonadism and the severity of hypogonadism.	Fathi AK	Journal of pediatric endocrinology & metabolism : JPEM	2012	PMID: 23155690
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
Isolated cryptorchidism: no evidence for involvement of genes underlying isolated hypogonadotropic hypogonadism.	Laitinen EM	Molecular and cellular endocrinology	2011	PMID: 21664240
GnRH receptor mutations in isolated gonadotropic deficiency.	Chevrier L	Molecular and cellular endocrinology	2011	PMID: 21645587
The role of gene defects underlying isolated hypogonadotropic hypogonadism in patients with constitutional delay of growth and puberty.	Vaaralahti K	Fertility and sterility	2011	PMID: 21292259
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
Digenic mutations account for variable phenotypes in idiopathic hypogonadotropic hypogonadism.	Pitteloud N	The Journal of clinical investigation	2007	PMID: 17235395
In vitro coexpression and pharmacological rescue of mutant gonadotropin-releasing hormone receptors causing hypogonadotropic hypogonadism in humans expressing compound heterozygous alleles.	Leaños-Miranda A	The Journal of clinical endocrinology and metabolism	2005	PMID: 15728205
Mutation Ala(171)Thr stabilizes the gonadotropin-releasing hormone receptor in its inactive conformation, causing familial hypogonadotropic hypogonadism.	Karges B	The Journal of clinical endocrinology and metabolism	2003	PMID: 12679486
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
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
Spontaneous pregnancy in a patient who was homozygous for the Q106R mutation in the gonadotropin-releasing hormone receptor gene.	Dewailly D	Fertility and sterility	2002	PMID: 12057744
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
The fertile eunuch variant of idiopathic hypogonadotropic hypogonadism: spontaneous reversal associated with a homozygous mutation in the gonadotropin-releasing hormone receptor.	Pitteloud N	The Journal of clinical endocrinology and metabolism	2001	PMID: 11397842
A new compound heterozygous mutation of the gonadotropin-releasing hormone receptor (L314X, Q106R) in a woman with complete hypogonadotropic hypogonadism: chronic estrogen administration amplifies the gonadotropin defect.	Kottler ML	The Journal of clinical endocrinology and metabolism	2000	PMID: 10999776
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
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
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
Subregional mapping of the human gonadotropin-releasing hormone receptor (GnRH-R) gene to 4q between the markers D4S392 and D4S409.	Kottler ML	Human genetics	1995	PMID: 7557974
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Text-mined citations for rs104893836 ...

These citations are identified by LitVar using the rs number, so they may include citations for more than one variant at this location. Please review the LitVar results carefully for your variant of interest.

Record last updated Nov 25, 2024

ClinVar Genomic variation as it relates to human health

NM_000406.3(GNRHR):c.317A>G (p.Gln106Arg)

Variant Details

Genes

Conditions - Germline

Submissions - Germline

Germline Functional Evidence

Citations for germline classification of this variant

Text-mined citations for rs104893836 ...