rs104893837

Variant summary

Our verdict is Likely pathogenic. Variant got 7 ACMG points: 8P and 1B. PP5_Very_StrongBP4

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 (★★).

Frequency

Genomes: 𝑓 0.0013 ( 0 hom., cov: 32)
Exomes 𝑓: 0.0016 ( 7 hom. )

Consequence

GNRHR
NM_000406.3 missense

Scores

7
7
4

Clinical Significance

Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:14U:1

Conservation

PhyloP100: 7.80
Variant links:
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)

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Likely_pathogenic. Variant got 7 ACMG points.

PP5
Variant 4-67740682-C-T is Pathogenic according to our data. Variant chr4-67740682-C-T is described in ClinVar as [Likely_pathogenic]. Clinvar id is 16024.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr4-67740682-C-T is described in Lovd as [Pathogenic].
BP4
Computational evidence support a benign effect (MetaRNN=0.07624191). . Strength limited to SUPPORTING due to the PP5.

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
GNRHRNM_000406.3 linkc.785G>A p.Arg262Gln missense_variant Exon 3 of 3 ENST00000226413.5 NP_000397.1 P30968-1
GNRHRNM_001012763.2 linkc.657G>A p.Thr219Thr synonymous_variant Exon 3 of 3 NP_001012781.1 P30968-2

Ensembl

Gene Transcript HGVSc HGVSp Effect Exon rank TSL MANE Protein Appris UniProt
GNRHRENST00000226413.5 linkc.785G>A p.Arg262Gln missense_variant Exon 3 of 3 1 NM_000406.3 ENSP00000226413.5 P30968-1

Frequencies

GnomAD3 genomes
AF:
0.00130
AC:
198
AN:
152048
Hom.:
0
Cov.:
32
show subpopulations
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
GnomAD3 exomes
AF:
0.00179
AC:
448
AN:
250854
Hom.:
1
AF XY:
0.00171
AC XY:
232
AN XY:
135646
show subpopulations
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 SAS exome
AF:
0.00216
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
show subpopulations
Gnomad4 AFR exome
AF:
0.0000901
Gnomad4 AMR exome
AF:
0.000268
Gnomad4 ASJ exome
AF:
0.000115
Gnomad4 EAS exome
AF:
0.00
Gnomad4 SAS exome
AF:
0.00214
Gnomad4 FIN exome
AF:
0.00605
Gnomad4 NFE exome
AF:
0.00150
Gnomad4 OTH exome
AF:
0.00128
GnomAD4 genome
AF:
0.00130
AC:
198
AN:
152166
Hom.:
0
Cov.:
32
AF XY:
0.00138
AC XY:
103
AN XY:
74390
show subpopulations
Gnomad4 AFR
AF:
0.000289
Gnomad4 AMR
AF:
0.000262
Gnomad4 ASJ
AF:
0.00
Gnomad4 EAS
AF:
0.00
Gnomad4 SAS
AF:
0.00145
Gnomad4 FIN
AF:
0.00473
Gnomad4 NFE
AF:
0.00181
Gnomad4 OTH
AF:
0.000948
Alfa
AF:
0.00154
Hom.:
0
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:14Uncertain:1
Revision: criteria provided, multiple submitters, no conflicts
LINK: link

Submissions by phenotype

Hypogonadotropic hypogonadism 7 with or without anosmia Pathogenic:10
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. -

Mar 02, 2023
Revvity Omics, Revvity
Significance: Pathogenic
Review Status: criteria provided, single submitter
Collection Method: clinical testing

- -

Jul 26, 2021
MGZ Medical Genetics Center
Significance: Likely pathogenic
Review Status: criteria provided, single submitter
Collection Method: clinical testing

- -

May 11, 2024
Fulgent Genetics, Fulgent Genetics
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. -

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

- -

Dec 01, 2006
OMIM
Significance: Pathogenic
Review Status: no assertion criteria provided
Collection Method: literature only

- -

Jun 20, 2019
Hadassah Hebrew University Medical Center
Significance: Pathogenic
Review Status: criteria provided, single submitter
Collection Method: clinical testing

- -

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 -

-
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). -

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
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

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

Publications

LitVar

Below is the list of publications found by LitVar. It may be empty.

Other links and lift over

dbSNP: rs104893837; hg19: chr4-68606400; API