ClinVar Genomic variation as it relates to human health
NM_000233.4(LHCGR):c.1733A>G (p.Asp578Gly)
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.1733A>G (p.Asp578Gly)
Variation ID: 14384 Accession: VCV000014384.11
- Type and length
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single nucleotide variant, 1 bp
- Location
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Cytogenetic: 2p16.3 2: 48688064 (GRCh38) [ NCBI UCSC ] 2: 48915203 (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 Jul 21, 2017 Feb 14, 2024 Jan 29, 2024 - HGVS
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Nucleotide Protein Molecular
consequenceNM_000233.4:c.1733A>G MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_000224.2:p.Asp578Gly missense NM_001198593.2:c.3441+16384T>C intron variant NC_000002.12:g.48688064T>C NC_000002.11:g.48915203T>C NG_008193.2:g.72678A>G NG_033050.2:g.163140T>C P22888:p.Asp578Gly - Protein change
- D578G
- Other names
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- Canonical SPDI
- NC_000002.12:48688063:T:C
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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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Allele frequency
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The frequency of the allele represented by this VCV record.
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Genes
Gene | OMIM | ClinGen Gene Dosage Sensitivity Curation |
Variation Viewer
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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
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The number of variants in ClinVar that are contained within this gene, with a link to view the list of variants. |
All
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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 |
- | 261 | |
STON1-GTF2A1L | - | - | - |
GRCh38 GRCh37 |
- | 302 |
Conditions - Germline
Condition
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The condition for this variant-condition (RCV) record in ClinVar. |
Classification
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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
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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
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The most recent date that a submitter evaluated this variant for the condition. |
Variation/condition record
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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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Jul 1, 1998 | RCV000015461.29 | |
Pathogenic (3) |
criteria provided, multiple submitters, no conflicts
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Jan 29, 2024 | RCV000517056.11 | |
Pathogenic (1) |
no assertion criteria provided
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Nov 9, 2012 | RCV000583503.1 | |
Pathogenic (1) |
criteria provided, single submitter
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Oct 31, 2018 | RCV000763499.2 |
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
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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
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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
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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
(Oct 31, 2018)
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criteria provided, single submitter
Method: clinical testing
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Gonadotropin-independent familial sexual precocity
Leydig cell agenesis
Affected status: unknown
Allele origin:
unknown
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Fulgent Genetics, Fulgent Genetics
Accession: SCV000894285.1
First in ClinVar: Mar 31, 2019 Last updated: Mar 31, 2019 |
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Pathogenic
(Aug 30, 2021)
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criteria provided, single submitter
Method: clinical testing
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not provided
Affected status: unknown
Allele origin:
unknown
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Athena Diagnostics
Accession: SCV000614017.4
First in ClinVar: Dec 19, 2017 Last updated: Dec 31, 2022 |
Comment:
This variant has not been reported in large, multi-ethnic general populations (http://gnomad.broadinstitute.org). This variant segregates with disease in at least one family. Assessment of experimental … (more)
This variant has not been reported in large, multi-ethnic general populations (http://gnomad.broadinstitute.org). This variant segregates with disease in at least one family. Assessment of experimental evidence suggests this variant results in abnormal protein function. This variant results in constitutively active cAMP signaling (PMID: 7692306, 7714085, 8943222, 21490077). (less)
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Pathogenic
(Jun 02, 2023)
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criteria provided, single submitter
Method: clinical testing
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Not Provided
Affected status: yes
Allele origin:
germline
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GeneDx
Accession: SCV001812796.2
First in ClinVar: Sep 08, 2021 Last updated: Jun 10, 2023 |
Comment:
Male members of a knock-in mouse model demonstrated precocious puberty (McGee et al., 2013); Published functional studies demonstrate that D578G is an activating variant (Shenker … (more)
Male members of a knock-in mouse model demonstrated precocious puberty (McGee et al., 2013); Published functional studies demonstrate that D578G is an activating variant (Shenker et al., 1993; Boot et al., 2011); Not observed in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 7692306, 8943222, 9703386, 7562970, 26040673, 7714085, 7527413, 30283825, 8855841, 23861372, 21490077) (less)
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Pathogenic
(Jan 29, 2024)
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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: SCV002218734.3
First in ClinVar: Mar 28, 2022 Last updated: Feb 14, 2024 |
Comment:
This sequence change replaces aspartic acid, which is acidic and polar, with glycine, which is neutral and non-polar, at codon 578 of the LHCGR protein … (more)
This sequence change replaces aspartic acid, which is acidic and polar, with glycine, which is neutral and non-polar, at codon 578 of the LHCGR protein (p.Asp578Gly). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individuals with autosomal dominant precocious puberty (PMID: 7692306, 30283825). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 14384). 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 with a positive predictive value of 80%. Experimental studies have shown that this missense change affects LHCGR function (PMID: 7692306, 21490077, 23861372). For these reasons, this variant has been classified as Pathogenic. (less)
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Pathogenic
(Jul 01, 1998)
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no assertion criteria provided
Method: literature only
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PRECOCIOUS PUBERTY, MALE-LIMITED
Affected status: not provided
Allele origin:
germline
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OMIM
Accession: SCV000035726.4
First in ClinVar: Apr 04, 2013 Last updated: Jul 21, 2017 |
Comment on evidence:
In individuals with familial male precocious puberty (FMPP; 176410) from 8 different families, Shenker et al. (1993) identified heterozygosity for a single A-to-G transition that … (more)
In individuals with familial male precocious puberty (FMPP; 176410) from 8 different families, Shenker et al. (1993) identified heterozygosity for a single A-to-G transition that resulted in substitution of glycine for aspartate at position 578 (D578G) in the sixth transmembrane helix of the LH receptor. Linkage of the mutation to the clinical disorder was supported by restriction-digest analysis. COS-7 cells expressing the mutant LH receptor exhibited markedly increased cyclic AMP production in the absence of agonist, suggesting that autonomous Leydig cell activity in this disorder is caused by a constitutively activated LH receptor. Kosugi et al. (1995) stated that the asp578-to-gly mutation had been found in affected males from 9 American FMPP families. Since 7 of the 9 originated in the southeastern United States, the possibility of a shared common ancestor was raised. For that reason, they analyzed genomic DNA from affected males from 6 new FMPP families: 2 from Germany, 3 from France, and 1 from the western United States with mixed Caucasian-Native American ancestry. None of the 6 new samples contained the asp578-to-gly mutation, as indicated by the absence of digestion with MspI. PCR products were then screened for heterozygous mutations by temperature-gradient gel electrophoresis. DNA fragments from 2 of the patients migrated abnormally. Direct sequencing of the PCR product from 1 affected German male revealed a heterozygous mutation of the type described in another European family by Kremer et al. (1993); see 152790.0002. In a screening of genomic DNA from 32 unrelated families with male-limited precocious puberty, Laue et al. (1995) found that 28 had the inherited form of the disorder, and of these, 24 had the D578G mutation. Four additional mutations were found among the remaining 4 families with the inherited form and in 4 sporadic cases of the disorder. Yano et al. (1994) found the asp578-to-gly mutation in a sporadic case of male precocious puberty in a Japanese patient. Kawate et al. (1995) found this same constitutively activating mutation of the LHCGR gene in a family with male-limited gonadotropin-independent precocious puberty (testotoxicosis). The family was ascertained through 2 affected brothers whose father had started puberty before his third birthday. His maternal uncle and maternal great uncle were also affected. Rosenthal et al. (1996) evaluated the pituitary-gonadal axis in a mother after 2 of her sons with familial male-limited precocious puberty were found to have the constitutively activating D578G mutation of the LHCGR gene. Ovarian function was normal in the 36-year-old mother as assessed by LH dynamics and FSH and androgen levels were normal throughout her menstrual cycle. Hormonal responses to acute GnRH agonist (nafarelin) challenge, chronic GnRH agonist administration, and dexamethasone were also normal. Studies of the affected sons on presentation at 2.4 and 3.5 years of age revealed that acute LH responses to nafarelin were in the hypogonadotropic range, and the FSH responses were prepubertal despite the presence of late pubertal testosterone blood levels. These data showed that the activating D578G mutation does not cause functional ovarian hyperandrogenism but only incomplete pubertal activation of Leydig cells consistent with the relatively low constitutive activity of this mutation. Martin et al. (1998) reported the development of a testicular seminoma in a 35-year-old man who had previously been diagnosed with familial male-limited precocious puberty and found to be heterozygous for the gain-of-function D578G mutation in the LHCGR gene. The authors stated that this represented the first case of a testicular germ cell tumor described in an FMPP patient. (less)
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Pathogenic
(Nov 09, 2012)
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no assertion criteria provided
Method: clinical testing
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Precocious puberty in males
Affected status: yes
Allele origin:
germline
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Clinical Molecular Genetics Laboratory, Johns Hopkins All Children's Hospital
Accession: SCV000692111.1
First in ClinVar: Feb 19, 2018 Last updated: Feb 19, 2018 |
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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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TESTOTOXICOSIS WITH AN EPISODIC COURSE: AN UNUSUAL CASE WITHIN A SERIES. | Nabhan ZM | AACE clinical case reports | 2019 | PMID: 31967000 |
A Case of Familial Male-Limited Precocious Puberty in a Child With Klinefelter Syndrome. | Cornacchia MA | Journal of the Endocrine Society | 2018 | PMID: 30283825 |
Constitutive luteinizing hormone receptor signaling causes sexual dysfunction and Leydig cell adenomas in male mice. | Hai L | Biology of reproduction | 2017 | PMID: 28339861 |
Infertility in Female Mice with a Gain-of-Function Mutation in the Luteinizing Hormone Receptor Is Due to Irregular Estrous Cyclicity, Anovulation, Hormonal Alterations, and Polycystic Ovaries. | Hai L | Biology of reproduction | 2015 | PMID: 26040673 |
Precocious puberty and Leydig cell hyperplasia in male mice with a gain of function mutation in the LH receptor gene. | McGee SR | Endocrinology | 2013 | PMID: 23861372 |
Mutation analysis of the LH receptor gene in Leydig cell adenoma and hyperplasia and functional and biochemical studies of activating mutations of the LH receptor gene. | Boot AM | The Journal of clinical endocrinology and metabolism | 2011 | PMID: 21490077 |
Testicular seminoma in a patient with a constitutively activating mutation of the luteinizing hormone/chorionic gonadotropin receptor. | Martin MM | European journal of endocrinology | 1998 | PMID: 9703386 |
The role of Asp578 in maintaining the inactive conformation of the human lutropin/choriogonadotropin receptor. | Kosugi S | The Journal of biological chemistry | 1996 | PMID: 8943222 |
Response to challenge with gonadotropin-releasing hormone agonist in a mother and her two sons with a constitutively activating mutation of the luteinizing hormone receptor--a clinical research center study. | Rosenthal IM | The Journal of clinical endocrinology and metabolism | 1996 | PMID: 8855841 |
Genetic heterogeneity of constitutively activating mutations of the human luteinizing hormone receptor in familial male-limited precocious puberty. | Laue L | Proceedings of the National Academy of Sciences of the United States of America | 1995 | PMID: 7892197 |
Characterization of heterogeneous mutations causing constitutive activation of the luteinizing hormone receptor in familial male precocious puberty. | Kosugi S | Human molecular genetics | 1995 | PMID: 7757065 |
A new constitutively activating point mutation in the luteinizing hormone/choriogonadotropin receptor gene in cases of male-limited precocious puberty. | Yano K | The Journal of clinical endocrinology and metabolism | 1995 | PMID: 7714085 |
Identification of constitutively activating mutation of the luteinising hormone receptor in a family with male limited gonadotrophin independent precocious puberty (testotoxicosis). | Kawate N | Journal of medical genetics | 1995 | PMID: 7562970 |
A sporadic case of male-limited precocious puberty has the same constitutively activating point mutation in luteinizing hormone/choriogonadotropin receptor gene as familial cases. | Yano K | The Journal of clinical endocrinology and metabolism | 1994 | PMID: 7527413 |
Cosegregation of missense mutations of the luteinizing hormone receptor gene with familial male-limited precocious puberty. | Kremer H | Human molecular genetics | 1993 | PMID: 8281137 |
A constitutively activating mutation of the luteinizing hormone receptor in familial male precocious puberty. | Shenker A | Nature | 1993 | PMID: 7692306 |
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Text-mined citations for rs121912518 ...
HelpRecord last updated Sep 01, 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.