rs104893844
Variant summary
Our verdict is Pathogenic. Variant got 11 ACMG points: 11P and 0B. PM5PP3PP5_Very_Strong
The NM_000406.3(GNRHR):c.268G>A(p.Glu90Lys) variant causes a missense change. The variant allele was found at a frequency of 0.0000062 in 1,614,064 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. E90D) has been classified as Likely pathogenic.
Frequency
Consequence
NM_000406.3 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Pathogenic. Variant got 11 ACMG points.
Transcripts
RefSeq
Ensembl
Frequencies
GnomAD3 genomes AF: 0.00000657 AC: 1AN: 152198Hom.: 0 Cov.: 32
GnomAD3 exomes AF: 0.0000358 AC: 9AN: 251334Hom.: 0 AF XY: 0.0000442 AC XY: 6AN XY: 135826
GnomAD4 exome AF: 0.00000616 AC: 9AN: 1461866Hom.: 0 Cov.: 32 AF XY: 0.00000688 AC XY: 5AN XY: 727238
GnomAD4 genome AF: 0.00000657 AC: 1AN: 152198Hom.: 0 Cov.: 32 AF XY: 0.0000135 AC XY: 1AN XY: 74348
ClinVar
Submissions by phenotype
Hypogonadotropic hypogonadism 7 with or without anosmia Pathogenic:3
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Variant summary: GNRHR c.268G>A (p.Glu90Lys) 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 3.6e-05 in 251334 control chromosomes. c.268G>A has been reported in the literature in individuals affected with isolated hypogonadotrophic hypogonadism in the homozygous state and segregated with disease in at least one family (e.g. Soderlund_2001). These data indicate that the variant is likely to be associated with disease. At least one publication reports experimental evidence that c.268G>A causes absent GnRH agonist binding and agonist-stimulated phosphoinositide turnover (Maya-Nunez_2002). At least one publication reports that mice with Gnrhr p.Glu90Lys have a similar phenotype to humans with hypogonadoropic hypogonadism (Stewart_2012). The following publications have been ascertained in the context of this evaluation (PMID: 11994356, 11318785, 22918878). ClinVar contains an entry for this variant (Variation ID: 16032). Based on the evidence outlined above, the variant was classified as pathogenic. -
not provided Pathogenic:2
This sequence change replaces glutamic acid, which is acidic and polar, with lysine, which is basic and polar, at codon 90 of the GNRHR protein (p.Glu90Lys). For these reasons, this variant has been classified as Pathogenic. Experimental studies have shown that this missense change affects GNRHR function (PMID: 11994356, 12107234, 22918878). Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Tolerated"; PolyPhen-2: "Probably Damaging"; Align-GVGD: "Class C0"). ClinVar contains an entry for this variant (Variation ID: 16032). This missense change has been observed in individual(s) with GNRHR-related conditions (PMID: 11318785; Invitae). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. It has also been observed to segregate with disease in related individuals. This variant is present in population databases (rs104893844, gnomAD 0.03%). -
Published functional studies demonstrate a damaging effect, specifically, in-vitro studies show protein surface expression, ligand-binding, and signal transduction are abolished (Maya-Nunez et al., 2002); This variant is associated with the following publications: (PMID: 12364481, 12107234, 14993385, 25531638, 11318785, 21633718, 14709805, 21527534, 19273112, 25857579, 21050923, 15886197, 22595961, 24324164, 24685158, 11994356, 22918878, 29744037, 24725593) -
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at