NM_000406.2(GNRHR):c.416G>A (p.Arg139His) AND Isolated GnRH Deficiency

replaced

Germline classification:: Pathogenic (1 submission)
Last evaluated:: Jun 14, 2016
Review status:: 1 star out of maximum of 4 stars
criteria provided, single submitter

Somatic classification of clinical impact:: None
Review status:: (0/4) 0 stars out of maximum of 4 stars
no assertion criteria provided

Somatic classification of oncogenicity:: None
Review status:: (0/4) 0 stars out of maximum of 4 stars
no assertion criteria provided

Record status:: current
Accession:: RCV000265551.1

Allele description

NM_000406.2(GNRHR):c.416G>A (p.Arg139His)

Gene:

GNRHR:gonadotropin releasing hormone receptor [Gene - OMIM - HGNC]

Variant type:

single nucleotide variant

Cytogenetic location:

4q13.2

Genomic location:

Preferred name:

NM_000406.2(GNRHR):c.416G>A (p.Arg139His)

HGVS:

NC_000004.12:g.67753920C>T
NG_009293.1:g.7167G>A
NM_000406.2:c.416G>A
NP_000397.1:p.Arg139His
NC_000004.11:g.68619638C>T
P30968:p.Arg139His

Protein change:

R139H; ARG139HIS

Links:

UniProtKB: P30968#VAR_019315; OMIM: 138850.0008; dbSNP: rs104893842

NCBI 1000 Genomes Browser:

rs104893842

Molecular consequence:

NM_000406.2:c.416G>A - missense variant - [Sequence Ontology: SO:0001583]

Condition(s)

Name:: Isolated GnRH Deficiency
Identifiers:: MedGen: CN239347

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV000450929	Illumina Clinical Services Laboratory,Illumina	criteria provided, single submitter (ICSL Variant Classification 20161018)	Pathogenic (Jun 14, 2016)	germline	clinical testing	PubMed (8) [See all records that cite these PMIDs] 11397871, 22724017, 12568864, 12364481, 22745237, 22405597, 22766261, 26207952 ICSL_Variant_Classification_20161018.pdf Citation Link

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV000450929

Illumina Clinical Services Laboratory,Illumina

criteria provided, single submitter

(ICSL Variant Classification 20161018)

Pathogenic
(Jun 14, 2016)

germline

clinical testing

PubMed (8)
[See all records that cite these PMIDs]

ICSL_Variant_Classification_20161018.pdf

Citation Link

Help

Summary from all submissions

Ethnicity	Origin	Affected	Individuals	Families	Chromosomes tested	Number Tested	Family history	Method
not provided	germline	unknown	not provided	not provided	not provided	not provided	not provided	clinical testing

Citations

PubMed

Two novel mutations in the gonadotropin-releasing hormone receptor gene in Brazilian patients with hypogonadotropic hypogonadism and normal olfaction.

Costa EM, Bedecarrats GY, Mendonca BB, Arnhold IJ, Kaiser UB, Latronico AC.

J Clin Endocrinol Metab. 2001 Jun;86(6):2680-6.

PubMed [citation]

PMID:: 11397871

Reversible congenital hypogonadotropic hypogonadism in patients with CHD7, FGFR1 or GNRHR mutations.

Laitinen EM, Tommiska J, Sane T, Vaaralahti K, Toppari J, Raivio T.

PLoS One. 2012;7(6):e39450. doi: 10.1371/journal.pone.0039450. Epub 2012 Jun 19.

PubMed [citation]

PMID:: 22724017
PMCID:: PMC3378565

See all PubMed Citations (8)

Details of each submission

From Illumina Clinical Services Laboratory,Illumina, SCV000450929.2

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (8)

Description

Across a selection of available literature, the c.416G>A (p.Arg139His) variant has been identified in a homozygous state in 10 isolated gonadotropin-releasing hormone (GnRH) deficiency patients, in a compound heterozygous state in at least 11 patients, 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 variant protein at the cell surface but complete elimination of GnRH-binding activity and activation of intracellular transduction pathways (Costa et al. 2001; LeaÃ±os-Miranda et al. 2002). Based on the evidence, the p.Arg139His variant is classified as pathogenic for isolated gonadotropin-releasing hormone (GnRH) deficiency.

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	unknown	not provided	not provided	not provided		not provided	not provided	not provided	not provided

Last Updated: Apr 17, 2019

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