NM_000406.3(GNRHR):c.317A>G (p.Gln106Arg) AND not provided

Germline classification:: Pathogenic (9 submissions)
Last evaluated:: Jan 21, 2024
Review status:: 2 stars out of maximum of 4 stars
criteria provided, multiple submitters, no conflicts

Somatic classification of clinical impact:: None
Review status:: (0/4) 0 stars out of maximum of 4 stars
no assertion criteria provided

Somatic classification of oncogenicity:: None
Review status:: (0/4) 0 stars out of maximum of 4 stars
no assertion criteria provided

Record status:: current
Accession:: RCV000255385.47

Allele description [Variation Report for NM_000406.3(GNRHR):c.317A>G (p.Gln106Arg)]

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

Gene:

GNRHR:gonadotropin releasing hormone receptor [Gene - OMIM - HGNC]

Variant type:

single nucleotide variant

Cytogenetic location:

4q13.2

Genomic location:

Preferred name:

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

HGVS:

NC_000004.12:g.67754019T>C
NG_009293.1:g.7068A>G
NM_000406.3:c.317A>GMANE SELECT
NM_001012763.2:c.317A>G
NP_000397.1:p.Gln106Arg
NP_000397.1:p.Gln106Arg
NP_001012781.1:p.Gln106Arg
NP_001012781.1:p.Gln106Arg
NC_000004.11:g.68619737T>C
NM_000406.2:c.317A>G
NM_001012763.1:c.317A>G
P30968:p.Gln106Arg

Protein change:

Q106R; GLN106ARG

Links:

UniProtKB: P30968#VAR_019313; OMIM: 138850.0001; dbSNP: rs104893836

NCBI 1000 Genomes Browser:

rs104893836

Molecular consequence:

NM_000406.3:c.317A>G - missense variant - [Sequence Ontology: SO:0001583]
NM_001012763.2:c.317A>G - missense variant - [Sequence Ontology: SO:0001583]

Observations:

Condition(s)

Synonyms:: none provided; RECLASSIFIED - ADRA2C POLYMORPHISM; RECLASSIFIED - ADRB1 POLYMORPHISM
Identifiers:: MedGen: C3661900

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV000321746	GeneDx	criteria provided, single submitter (GeneDx Variant Classification Process June 2021)	Pathogenic (Apr 11, 2022)	germline	clinical testing	Citation Link,
SCV000693150	CeGaT Center for Human Genetics Tuebingen	criteria provided, single submitter (CeGaT Center For Human Genetics Tuebingen Variant Classification Criteria Version 2)	Pathogenic (Apr 1, 2023)	germline	clinical testing	Citation Link,
SCV000931625	Labcorp Genetics (formerly Invitae), Labcorp	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Pathogenic (Jan 21, 2024)	germline	clinical testing	PubMed (13) [See all records that cite these PMIDs] 10999776, 11397871, 12057744, 20696889, 22745237, 23155690, 23643382, 26207952, 9371856, 12364481, 12574221, 15728205, 28492532
SCV001741838	Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen - VKGL Data-share Consensus	no assertion criteria provided	Pathogenic	germline	clinical testing
SCV001968940	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center - VKGL Data-share Consensus See additional submitters Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	no assertion criteria provided	Pathogenic	germline	clinical testing
SCV002070515	Genetic Services Laboratory, University of Chicago	criteria provided, single submitter (ACMG Guidelines, 2015)	Pathogenic (Jan 14, 2022)	germline	clinical testing	PubMed (1) [See all records that cite this PMID]
SCV002525663	Seattle Children's Hospital Molecular Genetics Laboratory, Seattle Children's Hospital	criteria provided, single submitter (ACMG Guidelines, 2015)	Pathogenic (Nov 15, 2021)	germline	clinical testing	PubMed (1) [See all records that cite this PMID]
SCV004229679	Athena Diagnostics	criteria provided, single submitter (Athena Diagnostics Criteria)	Pathogenic (Nov 15, 2022)	unknown	clinical testing	PubMed (18) [See all records that cite these PMIDs] 33223529, 30476149, 26207952, 25016926, 22745237, 10999776, 11397842, 11397871, 12364481, 12574221, 15728205, 17235395, 21292259, 21664240, 23155690, 9371856, 33968656, 26467025
SCV005198409	Clinical Genetics Laboratory, Skane University Hospital Lund	criteria provided, single submitter (ACMG Guidelines, 2015)	Pathogenic (Apr 4, 2023)	germline	clinical testing	PubMed (1) [See all records that cite this PMID]

Help

Summary from all submissions

Ethnicity	Origin	Affected	Individuals	Families	Chromosomes tested	Number Tested	Family history	Method
not provided	germline	yes	4	not provided	not provided	not provided	not provided	clinical testing
not provided	germline	unknown	not provided	not provided	not provided	not provided	not provided	clinical testing
not provided	unknown	unknown	not provided	not provided	not provided	not provided	not provided	clinical testing

Citations

PubMed

Spontaneous pregnancy in a patient who was homozygous for the Q106R mutation in the gonadotropin-releasing hormone receptor gene.

Dewailly D, Boucher A, Decanter C, Lagarde JP, Counis R, Kottler ML.

Fertil Steril. 2002 Jun;77(6):1288-91.

PubMed [citation]

PMID:: 12057744

Oligogenic basis of isolated gonadotropin-releasing hormone deficiency.

Sykiotis GP, Plummer L, Hughes VA, Au M, Durrani S, Nayak-Young S, Dwyer AA, Quinton R, Hall JE, Gusella JF, Seminara SB, Crowley WF Jr, Pitteloud N.

Proc Natl Acad Sci U S A. 2010 Aug 24;107(34):15140-4. doi: 10.1073/pnas.1009622107. Epub 2010 Aug 9.

PubMed [citation]

PMID:: 20696889
PMCID:: PMC2930591

See all PubMed Citations (23)

Details of each submission

From GeneDx, SCV000321746.12

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	not provided

Description

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)

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	yes	not provided	not provided	not provided		not provided	not provided	not provided	not provided

From CeGaT Center for Human Genetics Tuebingen, SCV000693150.31

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	4	not provided	not provided	clinical testing	not provided

Description

GNRHR: PM3:Very Strong, PP1:Moderate, PS3:Moderate, PM2:Supporting, BP4

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	yes	not provided	not provided	not provided		4	not provided	not provided	not provided

From Labcorp Genetics (formerly Invitae), Labcorp, SCV000931625.5

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (13)

Description

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.

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	unknown	not provided	not provided	not provided		not provided	not provided	not provided	not provided

From Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen - VKGL Data-share Consensus, SCV001741838.3

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	not provided

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	yes	not provided	not provided	not provided		not provided	not provided	not provided	not provided

From Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center - VKGL Data-share Consensus, SCV001968940.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	not provided

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	yes	not provided	not provided	not provided		not provided	not provided	not provided	not provided

From Genetic Services Laboratory, University of Chicago, SCV002070515.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (1)

Description

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).

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	yes	not provided	not provided	not provided		not provided	not provided	not provided	not provided

From Seattle Children's Hospital Molecular Genetics Laboratory, Seattle Children's Hospital, SCV002525663.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (1)

Description

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).

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	yes	not provided	not provided	not provided		not provided	not provided	not provided	not provided

From Athena Diagnostics, SCV004229679.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (18)

Description

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.

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	unknown	unknown	not provided	not provided	not provided		not provided	not provided	not provided	not provided

From Clinical Genetics Laboratory, Skane University Hospital Lund, SCV005198409.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (1)

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	yes	not provided	not provided	not provided		not provided	not provided	not provided	not provided

Last Updated: Jan 25, 2025

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