rs773279269
Variant names:
Your query was ambiguous. Multiple possible variants found:
Variant summary
Our verdict is Pathogenic. The variant received 18 ACMG points: 18P and 0B. PVS1PM2PP5_Very_Strong
The NM_000233.4(LHCGR):c.370C>T(p.Arg124*) variant causes a stop gained change. The variant allele was found at a frequency of 0.00000205 in 1,460,154 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★★). Variant results in nonsense mediated mRNA decay.
Frequency
Genomes: not found (cov: 32)
Exomes 𝑓: 0.0000021 ( 0 hom. )
Consequence
LHCGR
NM_000233.4 stop_gained
NM_000233.4 stop_gained
Scores
4
2
1
Clinical Significance
Conservation
PhyloP100: 3.73
Publications
2 publications found
Genes affected
LHCGR (HGNC:6585): (luteinizing hormone/choriogonadotropin receptor) This gene encodes the receptor for both luteinizing hormone and choriogonadotropin. This receptor belongs to the G-protein coupled receptor 1 family, and its activity is mediated by G proteins which activate adenylate cyclase. Mutations in this gene result in disorders of male secondary sexual character development, including familial male precocious puberty, also known as testotoxicosis, hypogonadotropic hypogonadism, Leydig cell adenoma with precocious puberty, and male pseudohermaphtoditism with Leydig cell hypoplasia. [provided by RefSeq, Jul 2008]
STON1-GTF2A1L (HGNC:30651): (STON1-GTF2A1L readthrough) STON1-GTF2A1L mRNAs are infrequent but naturally occurring read-through products of the neighboring STON1 and GTF2A1L genes. These transcripts encode fusion proteins composed of the vast majority of each of the individual elements, stonin 1 and general transcription factor IIA, 1-like. Alternative splicing results in multiple transcript variants. The significance of these read-through variants and the function of the resulting protein products have not yet been determined. [provided by RefSeq, Oct 2010]
GTF2A1L (HGNC:30727): (general transcription factor IIA subunit 1 like) The assembly and stability of the RNA polymerase II transcription pre-initiation complex on a eukaryotic core promoter involve the effects of transcription factor IIA (TFIIA) on the interaction between TATA-binding protein (TBP) and DNA. This gene encodes a germ cell-specific counterpart of the large (alpha/beta) subunit of general transcription factor TFIIA that is able to stabilize the binding of TBP to DNA and may be uniquely important to testis biology. Alternative splicing for this locus has been observed and two variants, encoding distinct isoforms, have been identified. Co-transcription of this gene and the neighboring upstream gene generates a rare transcript (SALF), which encodes a fusion protein comprised of sequence sharing identity with each individual gene product. [provided by RefSeq, Mar 2014]
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ACMG classification
Classification was made for transcript
Our verdict: Pathogenic. The variant received 18 ACMG points.
PVS1
Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.
PM2
Very rare variant in population databases, with high coverage;
PP5
Variant 2-48725689-G-A is Pathogenic according to our data. Variant chr2-48725689-G-A is described in CliVar as Pathogenic/Likely_pathogenic. Clinvar id is 492757.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr2-48725689-G-A is described in CliVar as Pathogenic/Likely_pathogenic. Clinvar id is 492757.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr2-48725689-G-A is described in CliVar as Pathogenic/Likely_pathogenic. Clinvar id is 492757.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr2-48725689-G-A is described in CliVar as Pathogenic/Likely_pathogenic. Clinvar id is 492757.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr2-48725689-G-A is described in CliVar as Pathogenic/Likely_pathogenic. Clinvar id is 492757.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr2-48725689-G-A is described in CliVar as Pathogenic/Likely_pathogenic. Clinvar id is 492757.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr2-48725689-G-A is described in CliVar as Pathogenic/Likely_pathogenic. Clinvar id is 492757.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr2-48725689-G-A is described in CliVar as Pathogenic/Likely_pathogenic. Clinvar id is 492757.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr2-48725689-G-A is described in CliVar as Pathogenic/Likely_pathogenic. Clinvar id is 492757.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr2-48725689-G-A is described in CliVar as Pathogenic/Likely_pathogenic. Clinvar id is 492757.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
Transcripts
RefSeq
Ensembl
| Gene | Transcript | HGVSc | HGVSp | Effect | Exon rank | TSL | MANE | Protein | Appris | UniProt |
|---|---|---|---|---|---|---|---|---|---|---|
| LHCGR | ENST00000294954.12 | c.370C>T | p.Arg124* | stop_gained | Exon 4 of 11 | 1 | NM_000233.4 | ENSP00000294954.6 | ||
| ENSG00000279956 | ENST00000602369.3 | n.295C>T | non_coding_transcript_exon_variant | Exon 3 of 13 | 5 | ENSP00000473498.1 |
Frequencies
GnomAD3 genomes
GnomAD3 genomes
Cov.:
32
GnomAD2 exomes AF: 0.00 AC: 0AN: 250980 AF XY: 0.00
GnomAD2 exomes
AF:
AC:
0
AN:
250980
AF XY:
Gnomad AFR exome
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Gnomad AMR exome
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Gnomad ASJ exome
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Gnomad EAS exome
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Gnomad FIN exome
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Gnomad NFE exome
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Gnomad OTH exome
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GnomAD4 exome AF: 0.00000205 AC: 3AN: 1460154Hom.: 0 Cov.: 30 AF XY: 0.00000275 AC XY: 2AN XY: 726546 show subpopulations
GnomAD4 exome
AF:
AC:
3
AN:
1460154
Hom.:
Cov.:
30
AF XY:
AC XY:
2
AN XY:
726546
show subpopulations
African (AFR)
AF:
AC:
0
AN:
33436
American (AMR)
AF:
AC:
0
AN:
44710
Ashkenazi Jewish (ASJ)
AF:
AC:
0
AN:
26106
East Asian (EAS)
AF:
AC:
0
AN:
39694
South Asian (SAS)
AF:
AC:
0
AN:
86210
European-Finnish (FIN)
AF:
AC:
0
AN:
53308
Middle Eastern (MID)
AF:
AC:
2
AN:
5758
European-Non Finnish (NFE)
AF:
AC:
1
AN:
1110612
Other (OTH)
AF:
AC:
0
AN:
60320
Allele Balance Distribution
Red line indicates average allele balance
Average allele balance: 0.442
Heterozygous variant carriers
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0
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0.00
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0.95
Allele balance
Age Distribution
Exome Het
Variant carriers
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GnomAD4 genome
GnomAD4 genome
Cov.:
32
Alfa
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Bravo
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ClinVar
Significance: Pathogenic/Likely pathogenic
Submissions summary: Pathogenic:4
Revision: criteria provided, multiple submitters, no conflicts
LINK: link
Submissions by phenotype
Leydig cell agenesis Pathogenic:2
Dec 19, 2024
Genomic Medicine Center of Excellence, King Faisal Specialist Hospital and Research Centre
Significance:Likely pathogenic
Review Status:criteria provided, single submitter
Collection Method:clinical testing
- -
Jan 02, 2018
Clinical Molecular Genetics Laboratory, Johns Hopkins All Children's Hospital
Significance:Pathogenic
Review Status:criteria provided, single submitter
Collection Method:clinical testing
- -
LHCGR-related disorder Pathogenic:1
May 06, 2024
PreventionGenetics, part of Exact Sciences
Significance:Likely pathogenic
Review Status:no assertion criteria provided
Collection Method:clinical testing
The LHCGR c.370C>T variant is predicted to result in premature protein termination (p.Arg124*). This variant was reported in at least one participant from a study of adults who underwent deep phenotyping and genome sequencing. Limited clinical information was provided (Hou et al. 2020. PubMed ID: 31980526). This variant has not been reported in a large population database, indicating this variant is rare. Nonsense variants in LHCGR are expected to be pathogenic. This variant is interpreted as likely pathogenic. -
not provided Pathogenic:1
May 28, 2020
GeneDx
Significance:Pathogenic
Review Status:criteria provided, single submitter
Collection Method:clinical testing
Nonsense variant predicted to result in protein truncation or nonsense mediated decay in a gene for which loss-of-function is a known mechanism of disease; Has not been previously published as pathogenic or benign to our knowledge; This variant is associated with the following publications: (PMID: 31980526) -
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
BayesDel_addAF
Pathogenic
D
BayesDel_noAF
Pathogenic
DANN
Uncertain
Eigen
Pathogenic
Eigen_PC
Pathogenic
FATHMM_MKL
Uncertain
D
PhyloP100
Vest4
GERP RS
Splicing
Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
Details are displayed if max score is > 0.2
DS_DL_spliceai
Position offset: -13
Find out detailed SpliceAI scores and Pangolin per-transcript scores at
Publications
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