rs104893844

Variant names:

Variant summary

Our verdict is Pathogenic. The variant received 14 ACMG points: 14P and 0B. PM1PM5PP2PP3PP5_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

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]

GNRHR links:

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

UBA6-DT links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Pathogenic. The variant received 14 ACMG points.

PM1

In a transmembrane_region Helical; Name=2 (size 19) in uniprot entity GNRHR_HUMAN there are 4 pathogenic changes around while only 0 benign (100%) in NM_000406.3

PM5

Other missense variant is known to change same aminoacid residue: Variant chrnull-null-null-null is described in UniProt as null.

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, hypogonadotropic hypogonadism 7 with or without anosmia.

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
GNRHR	NM_000406.3 link	c.268G>A	p.Glu90Lys	missense_variant	Exon 1 of 3	ENST00000226413.5	NP_000397.1	P30968-1
GNRHR	NM_001012763.2 link	c.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
GNRHR	ENST00000226413.5 link	c.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:

AN:

152198

Hom.:

Cov.:

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

GnomAD2 exomes

AF:

0.0000358

AC:

AN:

251334

AF XY:

0.0000442

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 FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00000616

AC:

AN:

1461866

Hom.:

Cov.:

AF XY:

0.00000688

AC XY:

AN XY:

727238

show subpopulations

Gnomad4 AFR exome

AF:

0.00

AC:

AN:

33480

Gnomad4 AMR exome

AF:

0.000201

AC:

AN:

44722

Gnomad4 ASJ exome

AF:

0.00

AC:

AN:

26136

Gnomad4 EAS exome

AF:

0.00

AC:

AN:

39698

Gnomad4 SAS exome

AF:

0.00

AC:

AN:

86256

Gnomad4 FIN exome

AF:

0.00

AC:

AN:

53420

Gnomad4 NFE exome

AF:

0.00

AC:

AN:

1111990

Gnomad4 Remaining exome

AF:

0.00

AC:

AN:

60396

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Exome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.00000657

AC:

AN:

152198

Hom.:

Cov.:

AF XY:

0.0000135

AC XY:

AN XY:

74348

show subpopulations

Gnomad4 AFR

AF:

0.00

AC:

AN:

Gnomad4 AMR

AF:

0.0000654

AC:

0.000065445

AN:

0.000065445

Gnomad4 ASJ

AF:

0.00

AC:

AN:

Gnomad4 EAS

AF:

0.00

AC:

AN:

Gnomad4 SAS

AF:

0.00

AC:

AN:

Gnomad4 FIN

AF:

0.00

AC:

AN:

Gnomad4 NFE

AF:

0.00

AC:

AN:

Gnomad4 OTH

AF:

0.00

AC:

AN:

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Genome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.00000465

Hom.:

Bravo

AF:

0.0000113

ExAC

AF:

0.0000330

AC:

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

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. -

May 01, 2002

OMIM

Significance:Pathogenic

Review Status:no assertion criteria provided

Collection Method:literature only

- -

not provided

Pathogenic:2

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) -

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%). -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.82

BayesDel_addAF

Benign

-0.013

BayesDel_noAF

Uncertain

0.040

CADD

Pathogenic

DANN

Pathogenic

1.0

DEOGEN2

Benign

0.26

T;.

Eigen

Pathogenic

0.75

Eigen_PC

Pathogenic

0.76

FATHMM_MKL

Uncertain

0.94

LIST_S2

Uncertain

0.90

D;D

M_CAP

Benign

0.070

MetaRNN

Pathogenic

0.77

D;D

MetaSVM

Uncertain

-0.066

MutationAssessor

Benign

1.6

L;L

PrimateAI

Uncertain

0.71

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

GERP RS

6.2

Varity_R

0.57

gMVP

0.87

Mutation Taster

=12/88

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

Publications

LitVar

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

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over