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
Consequence
NM_000406.3 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Likely_pathogenic. Variant got 7 ACMG points.
Transcripts
RefSeq
Ensembl
Frequencies
GnomAD3 genomes AF: 0.00130 AC: 198AN: 152048Hom.: 0 Cov.: 32
GnomAD3 exomes AF: 0.00179 AC: 448AN: 250854Hom.: 1 AF XY: 0.00171 AC XY: 232AN XY: 135646
GnomAD4 exome AF: 0.00155 AC: 2258AN: 1452324Hom.: 7 Cov.: 27 AF XY: 0.00155 AC XY: 1123AN XY: 723254
GnomAD4 genome AF: 0.00130 AC: 198AN: 152166Hom.: 0 Cov.: 32 AF XY: 0.00138 AC XY: 103AN XY: 74390
ClinVar
Submissions by phenotype
Hypogonadotropic hypogonadism 7 with or without anosmia Pathogenic:10
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. -
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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. -
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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 -
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
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) -
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
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See cases Pathogenic:1
ACMG categories: PM1,PP2,PP3,PP4,PP5,BP1 -
Amenorrhea Uncertain:1
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Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at