NM_000406.3:c.785G>A

Variant names:

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

Variant summary

Our verdict is Pathogenic. The variant received 16 ACMG points: 18P and 2B. PS3 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 (★★). ClinVar reports functional evidence for this variant: "SCV000916073: 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).; SCV001142337: 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).; SCV002767943: "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, PMID:12574221; SCV000583021: Published functional studies demonstrate a damaging effect on IP3 production and GnRH signal transmission (de Roux et al., 1997; Layman et al., 1998); 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; SCV002209386: Experimental studies have shown that this missense change affects GNRHR function (PMID:9371856, 9425890, 12574221).". 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:17 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 16 ACMG points.

• PS3: PS3 evidence extracted from ClinVar submissions: SCV000916073: 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).; SCV001142337: 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).; SCV002767943: "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, PMID:12574221; SCV000583021: Published functional studies demonstrate a damaging effect on IP3 production and GnRH signal transmission (de Roux et al., 1997; Layman et al., 1998); 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; SCV002209386: Experimental studies have shown that this missense change affects GNRHR function (PMID: 9371856, 9425890, 12574221).
• 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 AD,AR geneVariant has number of homozygotes lower than other variant known as pathogenic in the gene, so the strength is limited to Supporting.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_000406.3. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	GNRHR	NM_000406.3	MANE Select	c.785G>A	p.Arg262Gln	missense	Exon 3 of 3	NP_000397.1	P30968-1
	GNRHR	NM_001012763.2		c.657G>A	p.Thr219Thr	synonymous	Exon 3 of 3	NP_001012781.1	P30968-2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	GNRHR	ENST00000226413.5	TSL:1 MANE Select	c.785G>A	p.Arg262Gln	missense	Exon 3 of 3	ENSP00000226413.5	P30968-1
	GNRHR	ENST00000420975.2	TSL:1	c.657G>A	p.Thr219Thr	synonymous	Exon 3 of 3	ENSP00000397561.2	P30968-2
	UBA6-DT	ENST00000500538.7	TSL:1	n.1920+8337C>T		intron	N/A

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

ClinVar submissions

Significance: Pathogenic/Likely pathogenic

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
12	-	-	Hypogonadotropic hypogonadism 7 with or without anosmia (12)
2	-	-	not provided (2)
-	1	-	Amenorrhea (1)
1	-	-	Hypogonadotropic hypogonadism (1)
1	-	-	Pituitary hormone deficiency (1)
1	-	-	See cases (1)

Computational scores

Source: dbNSFP v4.9

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;