ClinVar Genomic variation as it relates to human health
NM_000233.4(LHCGR):c.1847C>A (p.Ser616Tyr)
The aggregate germline classification for this variant, typically for a monogenic or Mendelian disorder as in the ACMG/AMP guidelines, or for response to a drug. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the aggregate classification.
Stars represent the aggregate review status, or the level of review supporting the aggregate germline classification for this VCV record. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the review status. The number of submissions which contribute to this review status is shown in parentheses.
No data submitted for somatic clinical impact
No data submitted for oncogenicity
Variant Details
- Identifiers
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NM_000233.4(LHCGR):c.1847C>A (p.Ser616Tyr)
Variation ID: 14393 Accession: VCV000014393.5
- Type and length
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single nucleotide variant, 1 bp
- Location
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Cytogenetic: 2p16.3 2: 48687950 (GRCh38) [ NCBI UCSC ] 2: 48915089 (GRCh37) [ NCBI UCSC ]
- Timeline in ClinVar
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First in ClinVar Help The date this variant first appeared in ClinVar with each type of classification.
Last submission Help The date of the most recent submission for each type of classification for this variant.
Last evaluated Help The most recent date that a submitter evaluated this variant for each type of classification.
Germline Apr 4, 2013 Feb 14, 2024 Nov 21, 2023 - HGVS
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Nucleotide Protein Molecular
consequenceNM_000233.4:c.1847C>A MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_000224.2:p.Ser616Tyr missense NM_001198593.2:c.3441+16270G>T intron variant NC_000002.12:g.48687950G>T NC_000002.11:g.48915089G>T NG_008193.2:g.72792C>A NG_033050.2:g.163026G>T P22888:p.Ser616Tyr - Protein change
- S616Y
- Other names
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- Canonical SPDI
- NC_000002.12:48687949:G:T
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Functional
consequence HelpThe effect of the variant on RNA or protein function, based on experimental evidence from submitters.
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Global minor allele
frequency (GMAF) HelpThe global minor allele frequency calculated by the 1000 Genomes Project. The minor allele at this location is indicated in parentheses and may be different from the allele represented by this VCV record.
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0.00020 (T)
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Allele frequency
Help
The frequency of the allele represented by this VCV record.
Exome Aggregation Consortium (ExAC) 0.00002
The Genome Aggregation Database (gnomAD), exomes 0.00002
The Genome Aggregation Database (gnomAD) 0.00005
Trans-Omics for Precision Medicine (TOPMed) 0.00014
1000 Genomes Project 30x 0.00016
1000 Genomes Project 0.00020
Genes
Gene | OMIM | ClinGen Gene Dosage Sensitivity Curation |
Variation Viewer
Help
Links to Variation Viewer, a genome browser to view variation data from NCBI databases. |
Related variants | ||
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HI score
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The haploinsufficiency score for the gene, curated by ClinGen’s Dosage Sensitivity Curation task team. |
TS score
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The triplosensitivity score for the gene, curated by ClinGen’s Dosage Sensitivity Curation task team. |
Within gene
Help
The number of variants in ClinVar that are contained within this gene, with a link to view the list of variants. |
All
Help
The number of variants in ClinVar for this gene, including smaller variants within the gene and larger CNVs that overlap or fully contain the gene. |
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LHCGR | - | - |
GRCh38 GRCh37 |
- | 257 | |
STON1-GTF2A1L | - | - | - |
GRCh38 GRCh37 |
- | 297 |
Conditions - Germline
Condition
Help
The condition for this variant-condition (RCV) record in ClinVar. |
Classification
Help
The aggregate germline classification for this variant-condition (RCV) record in ClinVar. The number of submissions that contribute to this aggregate classification is shown in parentheses. (# of submissions) |
Review status
Help
The aggregate review status for this variant-condition (RCV) record in ClinVar. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the review status. |
Last evaluated
Help
The most recent date that a submitter evaluated this variant for the condition. |
Variation/condition record
Help
The RCV accession number, with most recent version number, for the variant-condition record, with a link to the RCV web page. |
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Pathogenic (1) |
no assertion criteria provided
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Feb 22, 1996 | RCV000015472.25 | |
Pathogenic/Likely pathogenic (2) |
criteria provided, multiple submitters, no conflicts
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Nov 21, 2023 | RCV003137526.2 | |
Pathogenic (1) |
criteria provided, single submitter
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Apr 30, 2023 | RCV002514103.2 |
Submissions - Germline
Classification
Help
The submitted germline classification for each SCV record. (Last evaluated) |
Review status
Help
Stars represent the review status, or the level of review supporting the submitted (SCV) record. This value is calculated by NCBI based on data from the submitter. Read our rules for calculating the review status. This column also includes a link to the submitter’s assertion criteria if provided, and the collection method. (Assertion criteria) |
Condition
Help
The condition for the classification, provided by the submitter for this submitted (SCV) record. This column also includes the affected status and allele origin of individuals observed with this variant. |
Submitter
Help
The submitting organization for this submitted (SCV) record. This column also includes the SCV accession and version number, the date this SCV first appeared in ClinVar, and the date that this SCV was last updated in ClinVar. |
More information
Help
This column includes more information supporting the classification, including citations, the comment on classification, and detailed evidence provided as observations of the variant by the submitter. |
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Pathogenic
(Nov 21, 2023)
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criteria provided, single submitter
Method: clinical testing
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Leydig cell agenesis
Affected status: unknown
Allele origin:
germline
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Women's Health and Genetics/Laboratory Corporation of America, LabCorp
Accession: SCV004223010.1
First in ClinVar: Jan 06, 2024 Last updated: Jan 06, 2024 |
Comment:
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. … (more)
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. (less)
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Likely pathogenic
(Jul 15, 2022)
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criteria provided, single submitter
Method: clinical testing
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Leydig cell agenesis
Affected status: yes
Allele origin:
germline
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Laboratorio de Genetica e Diagnostico Molecular, Hospital Israelita Albert Einstein
Accession: SCV003807605.1
First in ClinVar: Mar 04, 2023 Last updated: Mar 04, 2023 |
Comment:
ACMG classification criteria: PS3 supporting, PS4 moderated, PM2 moderated, PM3 supporting, PP3 supporting
Number of individuals with the variant: 1
Clinical Features:
Obesity (present) , Micropenis (present) , Cryptorchidism (present) , Hypospadias (present) , Tall stature (present) , Increased body weight (present) , Abnormal scrotum morphology (present)
Geographic origin: Brazil
Method: Paired-end whole-genome sequencing
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Pathogenic
(Apr 30, 2023)
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criteria provided, single submitter
Method: clinical testing
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not provided
Affected status: unknown
Allele origin:
germline
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Invitae
Accession: SCV003524768.2
First in ClinVar: Feb 07, 2023 Last updated: Feb 14, 2024 |
Comment:
This missense change has been observed in individuals with clinical features of autosomal recessive LHCGR-related conditions (PMID: 26246498, 27016457; Invitae). For these reasons, this variant … (more)
This missense change has been observed in individuals with clinical features of autosomal recessive LHCGR-related conditions (PMID: 26246498, 27016457; Invitae). For these reasons, this variant has been classified as Pathogenic. Experimental studies have shown that this missense change affects LHCGR function (PMID: 8559204, 11041448, 27533885). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is expected to disrupt LHCGR protein function. ClinVar contains an entry for this variant (Variation ID: 14393). This variant is present in population databases (rs121912525, gnomAD 0.009%). This sequence change replaces serine, which is neutral and polar, with tyrosine, which is neutral and polar, at codon 616 of the LHCGR protein (p.Ser616Tyr). (less)
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Pathogenic
(Feb 22, 1996)
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no assertion criteria provided
Method: literature only
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LEYDIG HYPOPLASIA, TYPE I
Affected status: not provided
Allele origin:
germline
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OMIM
Accession: SCV000035737.1
First in ClinVar: Apr 04, 2013 Last updated: Apr 04, 2013 |
Comment on evidence:
In a 6-year-old phenotypically male child who had been referred as a neonate for evaluation of micropenis (see 238320), Latronico et al. (1996) identified a … (more)
In a 6-year-old phenotypically male child who had been referred as a neonate for evaluation of micropenis (see 238320), Latronico et al. (1996) identified a C-to-A transversion of nucleotide 1847 of the LH-receptor cDNA, resulting in a change of codon 616 from one coding for serine (TCT) to one coding for tyrosine (TAT) within the seventh transmembrane region of the LH receptor. At birth, the length of the stretched phallus was 1.5 cm (more than 2.5 SD below the normal mean for age). Both testes were descended, with a volume of approximately 1 ml each. (less)
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Germline Functional Evidence
There is no functional evidence in ClinVar for this variation. If you have generated functional data for this variation, please consider submitting that data to ClinVar. |
Citations for germline classification of this variant
HelpTitle | Author | Journal | Year | Link |
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Novel Compound Heterozygous Variants in the LHCGR Gene in a Genetically Male Patient with Female External Genitalia. | Yan M | Journal of clinical research in pediatric endocrinology | 2019 | PMID: 30444213 |
Loss-of-Function Mutations in the Human Luteinizing Hormone Receptor Predominantly Cause Intracellular Retention. | Newton CL | Endocrinology | 2016 | PMID: 27533885 |
Novel homozygous nonsense mutations in the luteinizing hormone receptor (LHCGR) gene associated with 46,XY primary amenorrhea. | Ben Hadj Hmida I | Fertility and sterility | 2016 | PMID: 27016457 |
A new variant in signal peptide of the human luteinizing hormone receptor (LHCGR) affects receptor biogenesis causing leydig cell hypoplasia. | Vezzoli V | Human molecular genetics | 2015 | PMID: 26246498 |
LH receptor gene mutations and polymorphisms: an overview. | Piersma D | Molecular and cellular endocrinology | 2007 | PMID: 17030087 |
Inactivating mutations of G protein-coupled receptors and diseases: structure-function insights and therapeutic implications. | Tao YX | Pharmacology & therapeutics | 2006 | PMID: 16616374 |
An update of the pathophysiology of human gonadotrophin subunit and receptor gene mutations and polymorphisms. | Themmen AP | Reproduction (Cambridge, England) | 2005 | PMID: 16123233 |
Mutations of gonadotropins and gonadotropin receptors: elucidating the physiology and pathophysiology of pituitary-gonadal function. | Themmen APN | Endocrine reviews | 2000 | PMID: 11041448 |
Clinical manifestations of genetic defects affecting gonadotrophins and their receptors. | Conway GS | Clinical endocrinology | 1996 | PMID: 9039330 |
Compound heterozygous mutations of the luteinizing hormone receptor gene in Leydig cell hypoplasia. | Laue LL | Molecular endocrinology (Baltimore, Md.) | 1996 | PMID: 8843415 |
Brief report: testicular and ovarian resistance to luteinizing hormone caused by inactivating mutations of the luteinizing hormone-receptor gene. | Latronico AC | The New England journal of medicine | 1996 | PMID: 8559204 |
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Text-mined citations for rs121912525 ...
HelpRecord last updated Feb 20, 2024
This date represents the last time this VCV record was updated. The update may be due to an update to one of the included submitted records (SCVs), or due to an update that ClinVar made to the variant such as adding HGVS expressions or a rs number. So this date may be different from the date of the “most recent submission” reported at the top of this page.