NM_000406.3:c.806C>T
Variant summary
Our verdict is Uncertain significance. Variant got 4 ACMG points: 4P and 0B. PP3_ModeratePP5_Moderate
The NM_000406.3(GNRHR):c.806C>T(p.Thr269Met) variant causes a missense change. The variant allele was found at a frequency of 0.0000194 in 1,602,034 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 Pathogenic (★).
Frequency
Consequence
NM_000406.3 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Uncertain_significance. Variant got 4 ACMG points.
Transcripts
RefSeq
Ensembl
Frequencies
GnomAD3 genomes AF: 0.0000263 AC: 4AN: 152120Hom.: 0 Cov.: 32
GnomAD3 exomes AF: 0.0000119 AC: 3AN: 251190Hom.: 0 AF XY: 0.0000147 AC XY: 2AN XY: 135788
GnomAD4 exome AF: 0.0000186 AC: 27AN: 1449914Hom.: 0 Cov.: 27 AF XY: 0.0000180 AC XY: 13AN XY: 722200
GnomAD4 genome AF: 0.0000263 AC: 4AN: 152120Hom.: 0 Cov.: 32 AF XY: 0.0000135 AC XY: 1AN XY: 74300
ClinVar
Submissions by phenotype
Hypogonadotropic hypogonadism 7 with or without anosmia Pathogenic:2
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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 in this gene and is associated with hypogonadotropic hypogonadism 7 without anosmia (MIM#146110). (I) 0106 - This gene is associated with autosomal recessive disease. (I) 0200 - Variant is predicted to result in a missense amino acid change from threonine to methionine. (I) 0251 - This variant is heterozygous. (I) 0304 - Variant is present in gnomAD (v3) <0.01 for a recessive condition (4 heterozygotes, 0 homozygotes). (SP) 0502 - Missense variant with conflicting in silico predictions and uninformative conservation. (I) 0600 - Variant is located in the annotated 7 transmembrane receptor (rhodopsin family) domain (DECIPHER). (I) 0802 - This variant has moderate previous evidence of pathogenicity in unrelated individuals. This variant has been reported in three homozygous individuals with congenital hypogonadotropic hypogonadism (HH) or normosmic isolated HH. An additional two affected individuals were heterozygous for this variant, with no second hit identified in this gene (ClinVar, PMID: 30415482, PMID: 30476149, PMID: 27544332, PMID: 26708526, PMID: 22031817). (SP) 0901 - This variant has strong evidence for segregation with disease. This variant segregated in a single family with three affected siblings (PMID: 30415482). (SP) 1002 - This variant has moderate functional evidence supporting abnormal protein function. Transfected COS7 and HEK293 cells both demonstrated impaired protein function, including reduced protein binding and activation (PMID: 30476149). (SP) 1201 - Heterozygous variant detected in trans with a second pathogenic heterozygous variant (c.317A>G, p.(Gln106Arg)) in a recessive disease. (I) 1205 - This variant has been shown to be maternally inherited. (I) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign -
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at