NM_000233.4(LHCGR):c.1847C>A (p.Ser616Tyr) AND Leydig cell agenesis

Germline classification:: Pathogenic/Likely pathogenic (2 submissions)
Last evaluated:: Nov 21, 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:: RCV003137526.2

Allele description [Variation Report for NM_000233.4(LHCGR):c.1847C>A (p.Ser616Tyr)]

NM_000233.4(LHCGR):c.1847C>A (p.Ser616Tyr)

Genes:

STON1-GTF2A1L:STON1-GTF2A1L readthrough [Gene - HGNC]
LHCGR:luteinizing hormone/choriogonadotropin receptor [Gene - OMIM - HGNC]

Variant type:

single nucleotide variant

Cytogenetic location:

2p16.3

Genomic location:

Preferred name:

NM_000233.4(LHCGR):c.1847C>A (p.Ser616Tyr)

HGVS:

NC_000002.12:g.48687950G>T
NG_008193.2:g.72792C>A
NG_033050.2:g.163026G>T
NM_000233.4:c.1847C>AMANE SELECT
NM_001198593.2:c.3441+16270G>T
NP_000224.2:p.Ser616Tyr
NC_000002.11:g.48915089G>T
P22888:p.Ser616Tyr

Protein change:

S616Y; SER616TYR

Links:

UniProtKB: P22888#VAR_003562; OMIM: 152790.0009; dbSNP: rs121912525

NCBI 1000 Genomes Browser:

rs121912525

Molecular consequence:

NM_001198593.2:c.3441+16270G>T - intron variant - [Sequence Ontology: SO:0001627]
NM_000233.4:c.1847C>A - missense variant - [Sequence Ontology: SO:0001583]

Observations:

Condition(s)

Name:: Leydig cell agenesis
Synonyms:: LEYDIG CELL HYPOPLASIA WITH MALE PSEUDOHERMAPHRODITISM; LEYDIG CELL HYPOPLASIA, COMPLETE; HYPERGONADOTROPIC HYPOGONADISM, MALE, DUE TO LHCGR DEFECT; See all synonyms [MedGen]
Identifiers:: MONDO: MONDO:0009384; MedGen: C0266432; OMIM: 238320

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV003807605	Laboratorio de Genetica e Diagnostico Molecular, Hospital Israelita Albert Einstein	criteria provided, single submitter (ACMG Guidelines, 2015)	Likely pathogenic (Jul 15, 2022)	germline	clinical testing	PubMed (1) [See all records that cite this PMID]
SCV004223010	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	criteria provided, single submitter (LabCorp Variant Classification Summary - May 2015)	Pathogenic (Nov 21, 2023)	germline	clinical testing	PubMed (9) [See all records that cite these PMIDs] 8559204, 8843415, 17030087, 9039330, 16123233, 16616374, 27533885, 26246498, 30444213 Citation Link

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV003807605

Laboratorio de Genetica e Diagnostico Molecular, Hospital Israelita Albert Einstein

criteria provided, single submitter

(ACMG Guidelines, 2015)

Likely pathogenic
(Jul 15, 2022)

germline

clinical testing

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

SCV004223010

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

criteria provided, single submitter

(LabCorp Variant Classification Summary - May 2015)

Pathogenic
(Nov 21, 2023)

germline

clinical testing

PubMed (9)
[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	1	not provided	not provided	1	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

Brief report: testicular and ovarian resistance to luteinizing hormone caused by inactivating mutations of the luteinizing hormone-receptor gene.

Latronico AC, Anasti J, Arnhold IJ, Rapaport R, Mendonca BB, Bloise W, Castro M, Tsigos C, Chrousos GP.

N Engl J Med. 1996 Feb 22;334(8):507-12. No abstract available.

PubMed [citation]

PMID:: 8559204

See all PubMed Citations (10)

Details of each submission

From Laboratorio de Genetica e Diagnostico Molecular, Hospital Israelita Albert Einstein, SCV003807605.1

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

Description

ACMG classification criteria: PS3 supporting, PS4 moderated, PM2 moderated, PM3 supporting, PP3 supporting

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

From Women's Health and Genetics/Laboratory Corporation of America, LabCorp, SCV004223010.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (9)

Description

Variant summary: LHCGR c.1847C>A (p.Ser616Tyr) results in a non-conservative amino acid change located in the GPCR, rhodopsin-like, 7TM domain (IPR017452) 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 2e-05 in 250950 control chromosomes. c.1847C>A has been reported in the literature as a biallelic compound heterozygous or homozygous genotype in individuals affected with features of Leydig Cell Hypoplasia (example, Yan_2019, Newton_216, Vezzoli_2015). These data indicate that the variant is likely to be associated with disease. At least one publication reports experimental evidence evaluating an impact on protein function. The most pronounced variant effect results in severe intracellular retention and decreased hormone binding to the mutant receptor in-vitro (Newton_2016). The following publications have been ascertained in the context of this evaluation (PMID: 8559204, 8843415, 17030087, 9039330, 16123233, 16616374, 27533885, 26246498, 30444213). Two submitters have cited clinical-significance assessments for this variant to ClinVar after 2014. All submitters classified the variant as pathogenic/likely pathogenic. Based on the evidence outlined above, the variant was classified as 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: Sep 29, 2024

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