rs104893844

Variant summary

Our verdict is Pathogenic. Variant got 11 ACMG points: 11P and 0B. PM5PP3PP5_Very_Strong

The NM_000406.3(GNRHR):​c.268G>A​(p.Glu90Lys) variant causes a missense change. The variant allele was found at a frequency of 0.0000062 in 1,614,064 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic 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. E90D) has been classified as Likely pathogenic.

Frequency

Genomes: 𝑓 0.0000066 ( 0 hom., cov: 32)
Exomes 𝑓: 0.0000062 ( 0 hom. )

Consequence

GNRHR
NM_000406.3 missense

Scores

5
7
7

Clinical Significance

Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:5

Conservation

PhyloP100: 4.06
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 Pathogenic. Variant got 11 ACMG points.

PM5
Other missense variant is known to change same aminoacid residue: Variant chrnull-null-null-null is described in UniProt as null.
PP3
MetaRNN computational evidence supports a deleterious effect, 0.772
PP5
Variant 4-67754068-C-T is Pathogenic according to our data. Variant chr4-67754068-C-T is described in ClinVar as [Likely_pathogenic]. Clinvar id is 16032.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
GNRHRNM_000406.3 linkc.268G>A p.Glu90Lys missense_variant Exon 1 of 3 ENST00000226413.5 NP_000397.1 P30968-1
GNRHRNM_001012763.2 linkc.268G>A p.Glu90Lys missense_variant Exon 1 of 3 NP_001012781.1 P30968-2

Ensembl

Gene Transcript HGVSc HGVSp Effect Exon rank TSL MANE Protein Appris UniProt
GNRHRENST00000226413.5 linkc.268G>A p.Glu90Lys missense_variant Exon 1 of 3 1 NM_000406.3 ENSP00000226413.5 P30968-1

Frequencies

GnomAD3 genomes
AF:
0.00000657
AC:
1
AN:
152198
Hom.:
0
Cov.:
32
show subpopulations
Gnomad AFR
AF:
0.00
Gnomad AMI
AF:
0.00
Gnomad AMR
AF:
0.0000654
Gnomad ASJ
AF:
0.00
Gnomad EAS
AF:
0.00
Gnomad SAS
AF:
0.00
Gnomad FIN
AF:
0.00
Gnomad MID
AF:
0.00
Gnomad NFE
AF:
0.00
Gnomad OTH
AF:
0.00
GnomAD3 exomes
AF:
0.0000358
AC:
9
AN:
251334
Hom.:
0
AF XY:
0.0000442
AC XY:
6
AN XY:
135826
show subpopulations
Gnomad AFR exome
AF:
0.00
Gnomad AMR exome
AF:
0.000260
Gnomad ASJ exome
AF:
0.00
Gnomad EAS exome
AF:
0.00
Gnomad SAS exome
AF:
0.00
Gnomad FIN exome
AF:
0.00
Gnomad NFE exome
AF:
0.00
Gnomad OTH exome
AF:
0.00
GnomAD4 exome
AF:
0.00000616
AC:
9
AN:
1461866
Hom.:
0
Cov.:
32
AF XY:
0.00000688
AC XY:
5
AN XY:
727238
show subpopulations
Gnomad4 AFR exome
AF:
0.00
Gnomad4 AMR exome
AF:
0.000201
Gnomad4 ASJ exome
AF:
0.00
Gnomad4 EAS exome
AF:
0.00
Gnomad4 SAS exome
AF:
0.00
Gnomad4 FIN exome
AF:
0.00
Gnomad4 NFE exome
AF:
0.00
Gnomad4 OTH exome
AF:
0.00
GnomAD4 genome
AF:
0.00000657
AC:
1
AN:
152198
Hom.:
0
Cov.:
32
AF XY:
0.0000135
AC XY:
1
AN XY:
74348
show subpopulations
Gnomad4 AFR
AF:
0.00
Gnomad4 AMR
AF:
0.0000654
Gnomad4 ASJ
AF:
0.00
Gnomad4 EAS
AF:
0.00
Gnomad4 SAS
AF:
0.00
Gnomad4 FIN
AF:
0.00
Gnomad4 NFE
AF:
0.00
Gnomad4 OTH
AF:
0.00
Bravo
AF:
0.0000113
ExAC
AF:
0.0000330
AC:
4

ClinVar

Significance: Pathogenic/Likely pathogenic
Submissions summary: Pathogenic:5
Revision: criteria provided, multiple submitters, no conflicts
LINK: link

Submissions by phenotype

Hypogonadotropic hypogonadism 7 with or without anosmia Pathogenic:3
May 01, 2002
OMIM
Significance: Pathogenic
Review Status: no assertion criteria provided
Collection Method: literature only

- -

Apr 26, 2024
Fulgent Genetics, Fulgent Genetics
Significance: Pathogenic
Review Status: criteria provided, single submitter
Collection Method: clinical testing

- -

Apr 19, 2024
Women's Health and Genetics/Laboratory Corporation of America, LabCorp
Significance: Pathogenic
Review Status: criteria provided, single submitter
Collection Method: clinical testing

Variant summary: GNRHR c.268G>A (p.Glu90Lys) 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 3.6e-05 in 251334 control chromosomes. c.268G>A has been reported in the literature in individuals affected with isolated hypogonadotrophic hypogonadism in the homozygous state and segregated with disease in at least one family (e.g. Soderlund_2001). These data indicate that the variant is likely to be associated with disease. At least one publication reports experimental evidence that c.268G>A causes absent GnRH agonist binding and agonist-stimulated phosphoinositide turnover (Maya-Nunez_2002). At least one publication reports that mice with Gnrhr p.Glu90Lys have a similar phenotype to humans with hypogonadoropic hypogonadism (Stewart_2012). The following publications have been ascertained in the context of this evaluation (PMID: 11994356, 11318785, 22918878). ClinVar contains an entry for this variant (Variation ID: 16032). Based on the evidence outlined above, the variant was classified as pathogenic. -

not provided Pathogenic:2
Mar 19, 2022
Labcorp Genetics (formerly Invitae), Labcorp
Significance: Pathogenic
Review Status: criteria provided, single submitter
Collection Method: clinical testing

This sequence change replaces glutamic acid, which is acidic and polar, with lysine, which is basic and polar, at codon 90 of the GNRHR protein (p.Glu90Lys). For these reasons, this variant has been classified as Pathogenic. Experimental studies have shown that this missense change affects GNRHR function (PMID: 11994356, 12107234, 22918878). Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Tolerated"; PolyPhen-2: "Probably Damaging"; Align-GVGD: "Class C0"). ClinVar contains an entry for this variant (Variation ID: 16032). This missense change has been observed in individual(s) with GNRHR-related conditions (PMID: 11318785; Invitae). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. It has also been observed to segregate with disease in related individuals. This variant is present in population databases (rs104893844, gnomAD 0.03%). -

Feb 01, 2019
GeneDx
Significance: Likely pathogenic
Review Status: criteria provided, single submitter
Collection Method: clinical testing

Published functional studies demonstrate a damaging effect, specifically, in-vitro studies show protein surface expression, ligand-binding, and signal transduction are abolished (Maya-Nunez et al., 2002); This variant is associated with the following publications: (PMID: 12364481, 12107234, 14993385, 25531638, 11318785, 21633718, 14709805, 21527534, 19273112, 25857579, 21050923, 15886197, 22595961, 24324164, 24685158, 11994356, 22918878, 29744037, 24725593) -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Pathogenic
0.82
BayesDel_addAF
Benign
-0.013
T
BayesDel_noAF
Uncertain
0.040
CADD
Pathogenic
27
DANN
Pathogenic
1.0
DEOGEN2
Benign
0.26
T;.
Eigen
Pathogenic
0.75
Eigen_PC
Pathogenic
0.76
FATHMM_MKL
Uncertain
0.94
D
LIST_S2
Uncertain
0.90
D;D
M_CAP
Benign
0.070
D
MetaRNN
Pathogenic
0.77
D;D
MetaSVM
Uncertain
-0.066
T
MutationAssessor
Benign
1.6
L;L
PrimateAI
Uncertain
0.71
T
PROVEAN
Benign
-0.68
N;N
REVEL
Uncertain
0.49
Sift
Benign
0.034
D;T
Sift4G
Uncertain
0.018
D;T
Polyphen
1.0
D;D
Vest4
0.79
MutPred
0.84
Gain of ubiquitination at E90 (P = 0.0238);Gain of ubiquitination at E90 (P = 0.0238);
MVP
0.92
MPC
0.37
ClinPred
0.33
T
GERP RS
6.2
Varity_R
0.57
gMVP
0.87

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: rs104893844; hg19: chr4-68619786; API