4-67754019-T-C
Variant summary
Our verdict is Likely pathogenic. Variant got 7 ACMG points: 8P and 1B. PP5_Very_StrongBP4
The NM_000406.3(GNRHR):c.317A>G(p.Gln106Arg) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00354 in 1,613,870 control chromosomes in the GnomAD database, including 10 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 0.00234 AC: 356AN: 152184Hom.: 2 Cov.: 32
GnomAD3 exomes AF: 0.00284 AC: 714AN: 251236Hom.: 1 AF XY: 0.00289 AC XY: 393AN XY: 135772
GnomAD4 exome AF: 0.00366 AC: 5352AN: 1461568Hom.: 8 Cov.: 31 AF XY: 0.00362 AC XY: 2632AN XY: 727138
GnomAD4 genome 0.00234 AC: 356AN: 152302Hom.: 2 Cov.: 32 AF XY: 0.00216 AC XY: 161AN XY: 74474
ClinVar
Submissions by phenotype
Hypogonadotropic hypogonadism 7 with or without anosmia Pathogenic:14
ACMG categories: PS1,PS5,BP1 -
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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 for this gene and is associated with hypogonadotropic hypogonadism 7 without anosmia (MIM#146110). (I) 0106 - This gene is known to be associated with autosomal recessive disease. (I) 0200 - Variant is predicted to result in a missense amino acid change from glutamine to arginine (I). 0251 - This variant is heterozygous. (I) 0304 - Variant is present in gnomAD (v2) <0.01 for recessive indication (773 heterozygotes, 2 homozygotes). Sub-population: European, non-Finnish (517 heterozygotes, 1 homozygote). (SP) 0502 - Missense variant with conflicting in silico predictions and uninformative conservation. Minor amino acid change, very high conservation. (I) 0600 - Variant is located in the annotated domain, seven-transmembrane G protein-coupled receptor superfamily, extracellular loop (DECIPHER, NCBI). (I) 0705 - No comparable variants have previous evidence for pathogenicity. (I) 0801 - This variant has very strong previous evidence of pathogenicity in unrelated individuals. There are multiple reports of homozygous and compound heterozygous individuals with hypogonadotropic hypogonadism (PMIDs: 9371856, 12057744, 20389088, 22745237, 25016926, 26207952, 29182666, ClinVar, HGMD). It has been reported to be the most frequent variant causing hypogonadotropic hypogonadism, and also considered a founder variant in Europeans, African-American and South Asian populations (PMID: 26207952). There have also been several reports of heterozygous patients, with the possibility of environmental factors contributing to the phenotype (PMIDs: 22745237, 23650335). (SP) 0902 - This variant has moderate evidence for segregation with disease (PMIDs: 9371856, 30476149). (SP) 1002 - This variant has moderate functional evidence supporting abnormal protein function. In vitro studies showed decreased binding to its ligand, GNRH (PMID: 9371856, 15728205). (SP) 1201 - Heterozygous variant detected in trans with a second pathogenic heterozygous variant (c.806C>T, p.(Thr269Met)) in a recessive disease. (I) 1205 - This variant has been shown to be paternally inherited. (I) -
The GNRHR c.317A>G (p.Gln106Arg) missense variant has been reported in at least six studies and is found in a total of 32 individuals with isolated GnRH deficiency, including in four in a homozygous state, in 15 in a compound heterozygous state, and in 13 in a heterozygous state (de Roux 1997; Kottler et al. 2000; Pitteloud et al. 2001; Dewailly et al. 2002; Pitteloud et al. 2007; Gianetti et al. 2012). The affected individuals exhibited a range of phenotypes from mild to severe, with homozygotes exhibiting a milder phenotype than compound heterozygotes (Pitteloud et al. 2001; Dewailly et al. 2002; Bedecarrats et al. 2003). The p.Gln106Arg variant was also found in eight unaffected relatives (Pitteloud et al. 2001; Dewailly et al. 2002). The p.Gln106Arg variant was reported in two chromosomes of 604 control chromosomes and is reported at a frequency of 0.006015 in the Ashkenazi Jewish population of the Genome Aggregation Database. Two homozygous individuals are found in the Genome Aggregation Consortium, though these may be explained by homozygotes presenting a mild phenotype (Dewailly et al. 2002; Bedecarrats et al. 2003). In vitro expression analysis in CHO-K1 and COS-7 cells found p.Gln106Arg to have significantly reduced GNRH binding activity and reduced inositol phosphates binding compared to wildtype (de Roux 1997, Kottler et al. 2000; Leaños-Miranda et al. 2005). Based on the collective evidence, the p.Gln106Arg 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. -
Variant summary: GNRHR c.317A>G (p.Gln106Arg) 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 0.0028 in 251236 control chromosomes in the gnomAD database, including 1 homozygotes. c.317A>G has been reported in the literature in multiple bi-allelic and heterozygous individuals affected Kallmann syndrome and hypogonadotropic hypogonadism (Marcos_2014). This variant also segregated in a family affected with idiopathic hypogonadotropic hypogonadism (de Roux_1997). Multiple publications have reported experimental evidence that this variant reduced ligand binding (examples: de Roux_1997 and Leanos-Miranda_2002). The following publications have been ascertained in the context of this evaluation (PMID: 12364481, 9371856, 25077900). Fourteen clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 and all classified the variant as pathogenic/likely pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic. -
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NM_000406.2:c.317A>G in the GNRHR gene has an allele frequency of 0.006 in Ashkenazi Jewish subpopulation in the gnomAD database. The c.317A>G(p.Q106R) variant in the GNRHR gene has been reported previously in the compound heterozygous (Q106R/R262Q; P96S/Q106R; Q106R/S217R) and homozygous states in association with hypogonadotropic hypogonadism (PMID: 9371856; 22745237; 23643382). In vitro functional studies demonstrated that p.Q106R results in a loss of function of the receptor protein (PMID: 9371856). Taken together, we interprete this variant as Pathogenic/Likely pathogenic variant. ACMG/AMP Criteria applied: PS3; PM3_Strong; PP4. -
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not provided Pathogenic:9
The GNRHR p.Gln106Arg variant is known to cause partial loss-of-function of the GnRH receptor is the most common disease causing variant in the GNRHR gene and has been observed primarily in a homozygous state in individuals with IGD without anosmia (PMID: 22745237, PMID: 9371856 and others). While variants in GNRHR are typically homozygous or compound heterozygous, the p.Gln106Arg variant has been observed as a heterozygous change in individuals with Kallmann syndrome, normosmic idiopathic hypogonadotropic hypogonadism (nIHH), and adult-onset idiopathic hypogonadotropic hypogonadism (AOIHH) (PMID: 22745237, PMID: 20696). Individuals who are heterozygous for the p.Gln106Arg variant may also be asymptomatic carriers with normal puberty. This variant is present in the gnomAD database (allele frequency = 0.00275, gnomAD v2.1.1), but the prevalence of heterozygous GNRHR variants has been shown to be significantly higher among affected individuals compared to controls (PMID: 22745237). -
Published functional studies demonstrate a damaging effect by reducing the binding of GnRH-A and decreasing the activation of phospholipase C (de Roux et al., 1997); 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: 12364481, 25077900, 15728205, 22745237, 12574221, 26572316, 29431110, 28754744, 34426522, 31589614, 12679486, 23155690, 19820032, 10999776, 20696889, 23643382, 17235395, 9371856, 20389088, 10690855, 11397842, 10022417, 28348023, 26792935, 12057744, 29419413, 11397871, 28611058, 29182666, 30609409, 31980526, 30476149, 32870266, 19449676, 31200363, 34055685, 31130284, 34198905, 26207952) -
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This sequence change replaces glutamine, which is neutral and polar, with arginine, which is basic and polar, at codon 106 of the GNRHR protein (p.Gln106Arg). This variant is present in population databases (rs104893836, gnomAD 0.6%), and has an allele count higher than expected for a pathogenic variant. This missense change has been observed in individual(s) with varying degrees of HH or Kallman syndrome and hypogonadotropic hypogonadism (HH) (PMID: 9371856, 10999776, 11397871, 12057744, 20696889, 22745237, 23155690, 23643382, 26207952). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 16023). 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 not expected to disrupt GNRHR protein function with a negative predictive value of 80%. Experimental studies have shown that this missense change affects GNRHR function (PMID: 9371856, 12364481, 12574221, 15728205). For these reasons, this variant has been classified as Pathogenic. -
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The frequency of this variant in the general population is consistent with pathogenicity (http://gnomad.broadinstitute.org). This variant segregates with disease in multiple families. Assessment of experimental evidence suggests this variant results in abnormal protein function. (PMID: 9371856, 12364481, 12574221) In multiple individuals, this variant has been seen with a single recessive pathogenic variant in the same gene, suggesting this variant may also be pathogenic. -
GNRHR: PM3:Very Strong, PP1:Strong, PM2:Supporting, PS3:Supporting -
The p.Gln106Arg change affects a highly conserved amino acid residue located in a domain of the GNRHR protein that is known to be functional. The p.Gln106Arg substitution appears to be deleterious using several in-silico pathogenicity prediction tools (SIFT, PolyPhen2, Align GVGD, REVEL). This sequence change has been described in the gnomAD database with a population frequency of 0.40% in the non-Finnish European subpopulation (dbSNP rs104893836) and it is considered one of the most commonly observed pathogenic sequence change in this gene (PMID: 20389088). This sequence change has been reported to in individuals and families with hypogonadotropic hypogonadism (HH) (PMID: 9371856, 12057744, 11397871, 10999776) and has also been reported in several individuals Kallman syndrome (PMID: 20696889, 23155690, 23643382, 26207952, 22745237). In-vitro studies showed the binding of GnRH was reduced in cells transfected with the p.Gln106Arg sequence change (PMID: 9371856). -
Hypogonadotropic hypogonadism Pathogenic:1Other:1
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Variant classified as Pathogenic and reported on 01-08-2018 by Invitae. These coordinates are approximate and are based on NGS. GenomeConnect-Invitae Patient Insights Network assertions are reported exactly as they appear on the patient-provided report from the testing laboratory. Registry team members make no attempt to reinterpret the clinical significance of the variant. Phenotypic details are available under supporting information. -
GNRHR-related disorder Pathogenic:1
The GNRHR c.317A>G variant is predicted to result in the amino acid substitution p.Gln106Arg. This variant has been documented as causative for hypogonadotropic hypogonadism when present in the homozygous state or the compound heterozygous state with another pathogenic GNRHR variant (de Roux et al. 1997. PubMed ID: 9371856; Choi et al. 2005. PubMed ID: 26207952; Gianetti et al. 2012. PubMed ID: 22745237; Miraoui et al. 2013. PubMed ID: 23643382). This variant has also been detected in the heterozygous state in one man with hypogonadotropic hypogonadism (Table 2. Dwyer et al. 2023. PubMed ID: 36268624). In vitro functional studies have shown the p.Gln106Arg variant results in partial loss of function of the GNRHR receptor protein (de Roux et al. 1997. PubMed ID: 9371856; Leanos-Miranda et al. 2002. PubMed ID: 12364481; Gianetti et al. 2012. PubMed ID: 22745237). This variant is reported in 0.60% of alleles in individuals of Ashkenazi Jewish descent in gnomAD. This variant is interpreted as pathogenic. -
Isolated congenital hypogonadotropic hypogonadism Pathogenic:1
The p.Gln106Arg variant in GNRHR is an established pathogenic variant for hypogonadotropic hypogonadism (HH) and is the most common disease-causing HH variant in GNRHR (Kim 2010 PMID: 20389088). This variant has been identified in the homozygous and compound heterozygous state in multiple individuals with HH and segregated with disease in multiple affected relatives from multiple families. In addition, there are few reports of heterozygote carriers of the p.Gln106Arg variant presenting with isolated hypogonadotropic hypogonadism (Chevrier 2011 PMID: 21645587, Gianetti 2012 PMID: 22745237); however, it is unclear at this time if carrier status for this variant is associated with an increased risk for development of HH. This variant has been reported by other clinical laboratories in ClinVar (Variation ID: 16023) and has also been identified in 0.6% (185/29604) of Ashkenazi Jewish chromosomes including 10 total homozygotes by gnomAD (http://gnomad.broadinstitute.org, v.4.0.0). Although this variant has been seen in the general population, its frequency is low enough to be consistent with a recessive carrier frequency. In vitro functional assays indicate this variant leads to partial loss of GNRHR function (de Roux 1997 PMID: 9371856, Leanos-Miranda 2002 PMID: 12364481), correlating with the relatively milder phenotype observed in individuals who are homozygous for this variant. In summary, this variant meets criteria to be classified as pathogenic for autosomal recessive hypogonadotropic hypogonadism. ACMG/AMP Criteria applied: PM3_Very Strong, PP1_Strong, PM3. -
Inborn genetic diseases Pathogenic:1
The c.317A>G (p.Q106R) alteration is located in exon 1 (coding exon 1) of the GNRHR gene. This alteration results from an A to G substitution at nucleotide position 317, causing the glutamine (Q) at amino acid position 106 to be replaced by an arginine (R). Based on data from gnomAD, the G allele has an overall frequency of 0.275% (777/282638) total alleles studied. The highest observed frequency was 0.598% (62/10362) of Ashkenazi Jewish alleles. This variant has been identified in the homozygous state and in trans with another GNRHR variant in numerous individuals with features consistent with hypogonadotropic hypogonadism and has been reported to segregate with disease in several families (Dwyer, 2022; Saengkaew, 2021; Caburet, 2017; Marcos, 2014; Beneduzzi, 2014; Sykiotis, 2010; Karges, 2003; Dewailly, 2002; Pitteloud, 2001; de Roux, 1997). This amino acid position is highly conserved in available vertebrate species. In multiple assays testing GNRHR function, this variant has been shown to significantly reduce GnRH binding and decrease PLC activity as measured by decrease in intracellular IP production in response to GnRH (de Roux, 1997; Leanos-Miranda, 2005; Bedecarrats, 2003; Leanos-Miranda, 2002). This alteration is predicted to be deleterious by in silico analysis. Based on the available evidence, this alteration is classified as pathogenic. -
Infertility disorder Pathogenic:1
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Gonadotropin deficiency Pathogenic:1
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Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at