Submissions for variant NM_000406.3(GNRHR):c.797T>G (p.Leu266Arg)

gnomAD frequency: 0.00006  dbSNP: rs148499544

Total submissions: 3

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Labcorp Genetics (formerly Invitae), Labcorp	RCV002024394	SCV002308738	pathogenic	not provided	2024-10-21	criteria provided, single submitter	clinical testing	This sequence change replaces leucine, which is neutral and non-polar, with arginine, which is basic and polar, at codon 266 of the GNRHR protein (p.Leu266Arg). This variant is present in population databases (rs148499544, gnomAD 0.02%). This missense change has been observed in individual(s) with hypogonadotropic hypogonadism (PMID: 11297587, 19449676, 22035731; internal data). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. ClinVar contains an entry for this variant (Variation ID: 1519153). 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: 12107234, 12890567). For these reasons, this variant has been classified as Pathogenic.
Laboratorio de Genetica e Diagnostico Molecular, Hospital Israelita Albert Einstein	RCV003225761	SCV003806968	pathogenic	Hypogonadotropic hypogonadism 7 with or without anosmia	2022-08-19	criteria provided, single submitter	clinical testing	ACMG classification criteria: PS3 strong, PM2 supporting, PM3 strong, PP3 supporting
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV003225761	SCV003934498	likely pathogenic	Hypogonadotropic hypogonadism 7 with or without anosmia	2023-05-18	criteria provided, single submitter	clinical testing	Variant summary: GNRHR c.797T>G (p.Leu266Arg) results in a non-conservative amino acid change located in the GPCR, rhodopsin-like, 7TM domain (IPR01452) of the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 8e-06 in 251154 control chromosomes (gnomAD). c.797T>G has been reported in the literature in individuals affected with Hypogonadotropic Hypogonadism (examples: Beranova_2001, Bhagavath_2005 Quintos_2009, Quaynor_2011, Gianetti_2012, Marcos_2014). These data indicate that the variant may be associated with disease. Multiple reports have provided experimental evidence that this variant impairs normal protein function (examples: Beranova_2001, Janovick_2002, Bedecarrats_2003). The following publications have been ascertained in the context of this evaluation (PMID: 12107234, 11297587, 12890567, 9449676, 22745237, 16213849, 22035731, 25077900). Two clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 and classified the variant as pathogenic/likely pathogenic. Based on the evidence outlined above, the variant was classified as likely pathogenic.