4-67740682-C-T

Variant names:

• chr4-67740682-C-T
• rs104893837
• NM_000406.3:c.785G>A

Variant summary

Our verdict is Pathogenic. The variant received 12 ACMG points: 14P and 2B. PM1 PM5 PP2 PP3 PP5_Very_Strong BP4 BS2_Supporting

The NM_000406.3(GNRHR):​c.785G>A​(p.Arg262Gln) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00153 in 1,604,490 control chromosomes in the GnomAD database, including 7 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R262W) has been classified as Likely pathogenic.

• Frequency:
  • Genomes: 𝑓 0.0013 (0 hom., cov: 32)
  • Exomes 𝑓: 0.0016 (7 hom.)
• Consequence: GNRHR NM_000406.3 missense
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:16 U:1
• Conservation: PhyloP100: 7.80
• Publications: 72 publications found

Genes affected

GNRHR (HGNC:4421): (gonadotropin releasing hormone receptor) This gene encodes the receptor for type 1 gonadotropin-releasing hormone. This receptor is a member of the seven-transmembrane, G-protein coupled receptor (GPCR) family. It is expressed on the surface of pituitary gonadotrope cells as well as lymphocytes, breast, ovary, and prostate. Following binding of gonadotropin-releasing hormone, the receptor associates with G-proteins that activate a phosphatidylinositol-calcium second messenger system. Activation of the receptor ultimately causes the release of gonadotropic luteinizing hormone (LH) and follicle stimulating hormone (FSH). Defects in this gene are a cause of hypogonadotropic hypogonadism (HH). Alternative splicing results in multiple transcript variants encoding different isoforms. More than 18 transcription initiation sites in the 5' region and multiple polyA signals in the 3' region have been identified for this gene. [provided by RefSeq, Jul 2008]

UBA6-DT (HGNC:49083): (UBA6 divergent transcript)

ACMG classification

Our verdict: Pathogenic. The variant received 12 ACMG points.

• PM1: In a hotspot region, there are 2 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 3 uncertain in NM_000406.3
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr4-67740683-G-A is described in ClinVar as Pathogenic/Likely_pathogenic. ClinVar VariationId is 2151986.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• PP2: Missense variant in the gene, where a lot of missense mutations are associated with disease in ClinVar. The gene has 24 curated pathogenic missense variants (we use a threshold of 10). The gene has 1 curated benign missense variants. Gene score misZ: 0.30095 (below the threshold of 3.09). Trascript score misZ: 0.14426 (below the threshold of 3.09). GenCC associations: The gene is linked to hypogonadotropic hypogonadism 7 with or without anosmia, hypogonadotropic hypogonadism.
• PP3: Multiple lines of computational evidence support a deleterious effect 8: BayesDel_noAF, Cadd, Dann, Eigen, M_CAP, phyloP100way_vertebrate, REVEL, REVEL [when AlphaMissense, BayesDel_addAF, max_spliceai, FATHMM_MKL, MetaRNN, MutationTaster was below the threshold]
• PP5: Variant 4-67740682-C-T is Pathogenic according to our data. Variant chr4-67740682-C-T is described in ClinVar as Pathogenic/Likely_pathogenic. ClinVar VariationId is 16024.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP4: Computational evidence support a benign effect (MetaRNN=0.07624191). . Strength limited to SUPPORTING due to the PP5.
• BS2: High Homozygotes in GnomAdExome4 at 7 AR,AD geneVariant has number of homozygotes lower than other variant known as pathogenic in the gene, so the strength is limited to Supporting.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
GNRHR	NM_000406.3	c.785G>A	p.Arg262Gln	missense_variant	Exon 3 of 3	ENST00000226413.5	NP_000397.1
GNRHR	NM_001012763.2	c.657G>A	p.Thr219Thr	synonymous_variant	Exon 3 of 3		NP_001012781.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
GNRHR	ENST00000226413.5	c.785G>A	p.Arg262Gln	missense_variant	Exon 3 of 3	1	NM_000406.3	ENSP00000226413.5

Frequencies

GnomAD3 genomes AF: 0.00130 AC: 198 AN: 152048 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.000290

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000262

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00145

Gnomad FIN AF: 0.00473

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00181

Gnomad OTH AF: 0.000958

GnomAD2 exomes AF: 0.00179 AC: 448 AN: 250854 AF XY: 0.00171

Gnomad AFR exome AF: 0.000123

Gnomad AMR exome AF: 0.000231

Gnomad ASJ exome AF: 0.0000993

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00531

Gnomad NFE exome AF: 0.00215

Gnomad OTH exome AF: 0.00212

GnomAD4 exome AF: 0.00155 AC: 2258 AN: 1452324 Hom.: 7 Cov.: 27 AF XY: 0.00155 AC XY: 1123 AN XY: 723254

African (AFR) AF: 0.0000901 AC: 3 AN: 33284

American (AMR) AF: 0.000268 AC: 12 AN: 44718

Ashkenazi Jewish (ASJ) AF: 0.000115 AC: 3 AN: 26070

East Asian (EAS) AF: 0.00 AC: 0 AN: 39632

South Asian (SAS) AF: 0.00214 AC: 184 AN: 86074

European-Finnish (FIN) AF: 0.00605 AC: 323 AN: 53418

Middle Eastern (MID) AF: 0.000522 AC: 3 AN: 5742

European-Non Finnish (NFE) AF: 0.00150 AC: 1653 AN: 1103314

Other (OTH) AF: 0.00128 AC: 77 AN: 60072

GnomAD4 genome AF: 0.00130 AC: 198 AN: 152166 Hom.: 0 Cov.: 32 AF XY: 0.00138 AC XY: 103 AN XY: 74390

African (AFR) AF: 0.000289 AC: 12 AN: 41530

American (AMR) AF: 0.000262 AC: 4 AN: 15268

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5178

South Asian (SAS) AF: 0.00145 AC: 7 AN: 4828

European-Finnish (FIN) AF: 0.00473 AC: 50 AN: 10582

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.00181 AC: 123 AN: 67994

Other (OTH) AF: 0.000948 AC: 2 AN: 2110

Alfa AF: 0.00168 Hom.: 2

Bravo AF: 0.00107

TwinsUK AF: 0.00162 AC: 6

ALSPAC AF: 0.00208 AC: 8

ESP6500AA AF: 0.000227 AC: 1

ESP6500EA AF: 0.00221 AC: 19

ExAC AF: 0.00203 AC: 247

Asia WGS AF: 0.000578 AC: 2 AN: 3476

EpiCase AF: 0.00136

EpiControl AF: 0.00136

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:16 Uncertain:1

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Hypogonadotropic hypogonadism 7 with or without anosmia Pathogenic:12

May 11, 2024

Fulgent Genetics, Fulgent Genetics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

May 31, 2021

Genetics and Genomic Medicine Centre, NeuroGen Healthcare, NeuroGen Healthcare

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Sep 19, 2018

Illumina Laboratory Services, Illumina

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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. -

-

UNC Molecular Genetics Laboratory, University of North Carolina at Chapel Hill

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: research

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). -

Jul 26, 2021

MGZ Medical Genetics Center

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Jun 04, 2025

Institute of Medical Genetics and Applied Genomics, University Hospital Tübingen

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Mar 02, 2023

Revvity Omics, Revvity

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Jan 06, 2020

Reproductive Health Research and Development, BGI Genomics

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: curation

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. -

Jun 20, 2019

Hadassah Hebrew University Medical Center

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Apr 26, 2022

Department of Pathology and Laboratory Medicine, Sinai Health System

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: research

- -

Dec 01, 2006

OMIM

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

- -

May 06, 2021

Victorian Clinical Genetics Services, Murdoch Childrens Research Institute

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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 -

not provided Pathogenic:2

Feb 11, 2022

GeneDx

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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) -

Nov 29, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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). Invitae Evidence Modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) indicates that this missense variant is expected to disrupt GNRHR protein function with a positive predictive value of 80%. Experimental studies have shown that this missense change affects GNRHR function (PMID: 9371856, 9425890, 12574221). For these reasons, this variant has been classified as Pathogenic. -

Hypogonadotropic hypogonadism Pathogenic:1

Nov 11, 2024

NHS Central & South Genomic Laboratory Hub

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

See cases Pathogenic:1

Feb 22, 2017

Institute of Human Genetics, University Hospital Muenster

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

ACMG categories: PM1,PP2,PP3,PP4,PP5,BP1 -

Amenorrhea Uncertain:1

Mar 08, 2021

Yale Center for Mendelian Genomics, Yale University

Significance: Uncertain significance

Review Status: no assertion criteria provided

Collection Method: literature only

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.24
BayesDel_addAF	Benign	0.0071	T
BayesDel_noAF	Pathogenic	0.23
CADD	Pathogenic	29
DANN	Pathogenic	1.0
DEOGEN2	Uncertain	0.75	D
Eigen	Pathogenic	0.77
Eigen_PC	Pathogenic	0.77
FATHMM_MKL	Pathogenic	0.97	D
LIST_S2	Uncertain	0.88	D
M_CAP	Pathogenic	0.41	D
MetaRNN	Benign	0.076	T
MetaSVM	Uncertain	0.19	D
PhyloP100		7.8
PrimateAI	Uncertain	0.55	T
PROVEAN	Uncertain	-3.5	D
REVEL	Pathogenic	0.73
Sift	Uncertain	0.0030	D
Sift4G	Uncertain	0.0030	D
Polyphen		1.0	D
Vest4		0.93
MVP		0.89
MPC		0.34
ClinPred		0.087	T
GERP RS		5.4
Varity_R		0.73
gMVP		0.71
Mutation Taster		=3/97	disease causing (ClinVar)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.0		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs104893837; hg19: chr4-68606400;