ClinVar Miner

Submissions for variant NM_000406.2(GNRHR):c.317A>G (p.Gln106Arg) (rs104893836)

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Total submissions: 7
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
CeGaT Praxis fuer Humangenetik Tuebingen RCV000255385 SCV000693150 likely pathogenic not provided 2017-10-31 criteria provided, single submitter clinical testing
GeneDx RCV000255385 SCV000321746 pathogenic not provided 2018-08-23 criteria provided, single submitter clinical testing The Q106R variant in the GNRHR gene has been reported previously in the compound heterozygous and homozygous states in association with hypogonadotropic hypogonadism, (de Roux et al., 1997; Gianetti et al., 2012; Miraoui et al., 2013; Dwyer et al., 2016). The Q106R variant is observed in 61/10142 (0.6%) alleles from individuals of Ashkenazi Jewish background and in 751/276954 (0.27%) total alleles in large population cohorts, and two individuals have been reported to be homozygous (Lek et al., 2016). The Q106R variant is a semi-conservative amino acid substitution, which may impact secondary protein structure as these residues differ in some properties. In vitro functional studies demonstrated that Q106R results in a loss of function of the receptor protein (de Roux et al., 1997). We interpret Q106R as a pathogenic variant.
Genomic Research Center,Shahid Beheshti University of Medical Sciences RCV000662016 SCV000784348 pathogenic Gonadotropin deficiency 2018-03-05 criteria provided, single submitter clinical testing
Illumina Clinical Services Laboratory,Illumina RCV000190591 SCV000916074 pathogenic Hypogonadotropic hypogonadism 7 with or without anosmia 2018-09-20 criteria provided, single submitter clinical testing 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.
Invitae RCV000255385 SCV000931625 pathogenic not provided 2018-12-18 criteria provided, single submitter clinical testing This sequence change replaces glutamine with arginine at codon 106 of the GNRHR protein (p.Gln106Arg). The glutamine residue is highly conserved and there is a small physicochemical difference between glutamine and arginine. This variant is present in population databases (rs104893836, ExAC 0.4%), and has an allele count higher than expected for a pathogenic variant (PMID: 28166811). This variant has been reported to segregate with hypogonadotropic hypogonadism (HH) in multiple families (PMID: 9371856, 12057744, 11397871, 10999776) and has been reported as homozygous or in combination with a second variant in several individuals affected with varying degrees of HH or Kallman syndrome (PMID: 20696889, 23155690, 23643382, 26207952, 22745237). ClinVar contains an entry for this variant (Variation ID: 16023). Experimental studies have shown that this missense change leads to partial loss of GNRHR function (PMID: 9371856, 12574221, 15728205, 12364481). For these reasons, this variant has been classified as Pathogenic.
Laboratory for Molecular Medicine,Partners HealthCare Personalized Medicine RCV000599632 SCV000245617 pathogenic Isolated congenital hypogonadotropic hypogonadism 2014-08-01 criteria provided, single submitter clinical testing The p.Gln106Arg variant in GNRHR is an established pathogenic variant for hypogo nadotropic hypogonadism (HH) and is the most common disease-causing HH variant i n GNRHR (Kim 2010). In vitro functional assays indicate this variant leads to pa rtial loss of GNRHR function (de Roux 1997, Leanos-Miranda 2002), correlating wi th the relatively milder phenotype observed in individuals who are homozygous fo r this variant. This variant has been identified in the homozygous and compound heterozygous state in multiple individuals with HH and segregated with disease i n multiple affected relatives from multiple families. In addition, there are few reports of heterozygote carriers of the p.Gln106Arg variant presenting with iso lated hypogonadotropic hypogonadism (Chevrier 2011, Gianetti 2012); 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 identified in 0.2% (751/276954) of chromosomes by the Genome Aggregation Database (gnomAD, http://e xac.broadinstitute.org). Although this variant has been seen in the general popu lation, its frequency is low enough to be consistent with a recessive carrier fr equency. In summary, this variant meets criteria to be classified as pathogeni c for HH in an autosomal recessive manner. ACMG/AMP Criteria applied: PM3_Very S trong, PP1_Strong, PM3.
OMIM RCV000190591 SCV000037669 pathogenic Hypogonadotropic hypogonadism 7 with or without anosmia 2007-02-01 no assertion criteria provided literature only

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