NM_000406.3(GNRHR):c.797T>G (p.Leu266Arg) AND Hypogonadotropic hypogonadism 7 with or without anosmia

Germline classification:: Pathogenic/Likely pathogenic (2 submissions)
Last evaluated:: May 18, 2023
Review status:: 2 stars out of maximum of 4 stars
criteria provided, multiple submitters, no conflicts

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:: RCV003225761.9

Allele description [Variation Report for NM_000406.3(GNRHR):c.797T>G (p.Leu266Arg)]

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

Gene:

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

Variant type:

single nucleotide variant

Cytogenetic location:

4q13.2

Genomic location:

Preferred name:

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

HGVS:

NC_000004.12:g.67740670A>C
NG_009293.1:g.20417T>G
NM_000406.3:c.797T>GMANE SELECT
NM_001012763.2:c.669T>G
NP_000397.1:p.Leu266Arg
NP_001012781.1:p.Ser223=
NC_000004.11:g.68606388A>C
NM_000406.2:c.797T>G

Protein change:

L266R

Links:

dbSNP: rs148499544

NCBI 1000 Genomes Browser:

rs148499544

Molecular consequence:

NM_000406.3:c.797T>G - missense variant - [Sequence Ontology: SO:0001583]
NM_001012763.2:c.669T>G - synonymous variant - [Sequence Ontology: SO:0001819]

Condition(s)

Name:: Hypogonadotropic hypogonadism 7 with or without anosmia (HH7)
Synonyms:: HYPOGONADOTROPIC HYPOGONADISM 7 WITHOUT ANOSMIA
Identifiers:: MONDO: MONDO:0007794; MedGen: C0342384; Orphanet: 432; OMIM: 146110

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV003806968	Laboratorio de Genetica e Diagnostico Molecular, Hospital Israelita Albert Einstein	criteria provided, single submitter (ACMG Guidelines, 2015)	Pathogenic (Aug 19, 2022)	germline	clinical testing	PubMed (1) [See all records that cite this PMID]
SCV003934498	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	criteria provided, single submitter (LabCorp Variant Classification Summary - May 2015)	Likely pathogenic (May 18, 2023)	germline	clinical testing	PubMed (8) [See all records that cite these PMIDs] 25077900, 22035731, 12890567, 11297587, 16213849, 22745237, 12107234, 9449676 Citation Link

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV003806968

Laboratorio de Genetica e Diagnostico Molecular, Hospital Israelita Albert Einstein

criteria provided, single submitter

(ACMG Guidelines, 2015)

Pathogenic
(Aug 19, 2022)

germline

clinical testing

PubMed (1)
[See all records that cite this PMID]

SCV003934498

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

criteria provided, single submitter

(LabCorp Variant Classification Summary - May 2015)

Likely pathogenic
(May 18, 2023)

germline

clinical testing

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

Citation Link

Help

Summary from all submissions

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

Citations

PubMed

Standards and guidelines for the interpretation of sequence variants: a joint consensus recommendation of the American College of Medical Genetics and Genomics and the Association for Molecular Pathology.

Richards S, Aziz N, Bale S, Bick D, Das S, Gastier-Foster J, Grody WW, Hegde M, Lyon E, Spector E, Voelkerding K, Rehm HL; ACMG Laboratory Quality Assurance Committee..

Genet Med. 2015 May;17(5):405-24. doi: 10.1038/gim.2015.30. Epub 2015 Mar 5.

PubMed [citation]

PMID:: 25741868
PMCID:: PMC4544753

The prevalence of CHD7 missense versus truncating mutations is higher in patients with Kallmann syndrome than in typical CHARGE patients.

Marcos S, Sarfati J, Leroy C, Fouveaut C, Parent P, Metz C, Wolczynski S, Gérard M, Bieth E, Kurtz F, Verier-Mine O, Perrin L, Archambeaud F, Cabrol S, Rodien P, Hove H, Prescott T, Lacombe D, Christin-Maitre S, Touraine P, Hieronimus S, Dewailly D, et al.

J Clin Endocrinol Metab. 2014 Oct;99(10):E2138-43. doi: 10.1210/jc.2014-2110. Epub 2014 Jul 31. Erratum in: J Clin Endocrinol Metab. 2015 Jan;100(1):317.

PubMed [citation]

PMID:: 25077900

See all PubMed Citations (9)

Details of each submission

From Laboratorio de Genetica e Diagnostico Molecular, Hospital Israelita Albert Einstein, SCV003806968.2

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

Description

ACMG classification criteria: PS3 strong, PM2 supporting, PM3 strong, PP3 supporting

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

From Women's Health and Genetics/Laboratory Corporation of America, LabCorp, SCV003934498.1

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

Description

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.

#	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: Nov 3, 2024

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