Submissions for variant NM_000406.3(GNRHR):c.416G>A (p.Arg139His)

gnomAD frequency: 0.00021  dbSNP: rs104893842

Total submissions: 9

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Illumina Laboratory Services, Illumina	RCV000030914	SCV000450929	pathogenic	Hypogonadotropic hypogonadism 7 with or without anosmia	2016-09-14	criteria provided, single submitter	clinical testing	The GNRHR c.416G>A (p.Arg139His) missense variant has been identified in a homozygous state in ten individuals and in a compound heterozygous state in at least 11 individuals with isolated gonadotropin-releasing hormone (GnRH) deficiency, and in a heterozygous state in five unaffected family members (Costa et al. 2001; Wolczynski et al. 2003; Laitinen et al. 2012; Gianetti et al. 2012; Hero et al. 2012; Gurbuz et al. 2012; Choi et al. 2015). The p.Arg139His variant was absent from 422 controls and is reported at a frequency of 0.00076 in the European (Finnish) population of the Exome Aggregation Consortium. Functional studies in COS-7 cells demonstrated normal localization of the mutant protein at the cell surface but complete elimination of GnRH-binding activity and activation of intracellular transduction pathways (Costa et al. 2001; Leanos-Miranda et al. 2002). Based on the evidence, the p.Arg139His 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.
GeneDx	RCV000497820	SCV000589592	pathogenic	not provided	2022-04-11	criteria provided, single submitter	clinical testing	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, 11397871, 26207952, 22745237, 32763379, 31589614, 26044071, 12667096, 23155690, 21645587, 34426522, 20207726, 16213849, 24117998, 21736917, 22766261, 25016926, 20389088, 14689055, 22405597, 21717411, 31200363, 30476149, 32222824, 27544332, 34198905)
Centre for Mendelian Genomics, University Medical Centre Ljubljana	RCV000030914	SCV001367651	pathogenic	Hypogonadotropic hypogonadism 7 with or without anosmia	2020-03-23	criteria provided, single submitter	clinical testing	This variant was classified as: Pathogenic. The following ACMG criteria were applied in classifying this variant: PS3,PS4_MOD,PM2,PM3,PP2,PP3,PP4.
Labcorp Genetics (formerly Invitae), Labcorp	RCV000497820	SCV001590395	pathogenic	not provided	2023-12-18	criteria provided, single submitter	clinical testing	This sequence change replaces arginine, which is basic and polar, with histidine, which is basic and polar, at codon 139 of the GNRHR protein (p.Arg139His). This variant is present in population databases (rs104893842, gnomAD 0.05%). This missense change has been observed in individuals with hypogonadotropic hypogonadism (PMID: 11397871, 22724017, 25016926, 26207952, 27544332). It is commonly reported in individuals of Brazilian ancestry (PMID: 11397871, 22724017, 25016926, 26207952, 27544332). ClinVar contains an entry for this variant (Variation ID: 16030). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae 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: 11397871, 12364481). For these reasons, this variant has been classified as Pathogenic.
CeGaT Center for Human Genetics Tuebingen	RCV000497820	SCV001961834	pathogenic	not provided	2021-08-01	criteria provided, single submitter	clinical testing
Fulgent Genetics, Fulgent Genetics	RCV000030914	SCV002783899	pathogenic	Hypogonadotropic hypogonadism 7 with or without anosmia	2021-11-16	criteria provided, single submitter	clinical testing
Neuberg Centre For Genomic Medicine, NCGM	RCV000030914	SCV004176413	pathogenic	Hypogonadotropic hypogonadism 7 with or without anosmia	2023-03-01	criteria provided, single submitter	clinical testing
OMIM	RCV000030914	SCV000037677	pathogenic	Hypogonadotropic hypogonadism 7 with or without anosmia	2001-06-01	no assertion criteria provided	literature only
Genetic Services Laboratory, University of Chicago	RCV000497820	SCV003839564	pathogenic	not provided	2022-12-19	no assertion criteria provided	clinical testing	DNA sequence analysis of the GNRHR gene demonstrated a sequence change, c.416G>A , in exon 1 that results in an amino acid change, p.Arg139His. The p.Arg139His change affects a highly conserved amino acid residue located in a domain of the GNRHR protein that is known to be functional. The p.Arg139His substitution appears to be deleterious using several in-silico pathogenicity prediction tools (SIFT, PolyPhen2, Align GVGD, REVEL). This pathogenic sequence change has previously been described in individuals with hypogonadotropic hypogonadism and is commonly reported in individuals of Brazilian ancestry (PMID: 11397871, 22724017, 25016926, 26207952, 27544332). This sequence change has been described in the gnomAD database with a frequency of 0.055% in the European subpopulation (dbSNP rs104893842). These collective evidences indicate that this sequence change is pathogenic.