NM_000233.4:c.1118C>T

Variant names:

• chr2-48688679-G-A
• rs121912528
• NM_000233.4:c.1118C>T

Variant summary

Our verdict is Likely pathogenic. The variant received 8 ACMG points: 8P and 0B. PM2 PP2 PP3_Strong PP5

The NM_000233.4(LHCGR):​c.1118C>T​(p.Ala373Val) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Pathogenic (no stars).

• Frequency: Genomes: not found (cov: 32)
• Consequence: LHCGR NM_000233.4 missense
• Clinical Significance: Likely pathogenic criteria provided, single submitter P:2
• Conservation: PhyloP100: 9.97
• Publications: 11 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]

ENSG00000279956 (HGNC:):

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]

ACMG classification

Our verdict: Likely_pathogenic. The variant received 8 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP2: Missense variant in the gene, where a lot of missense mutations are associated with disease in ClinVar. The gene has 29 curated pathogenic missense variants (we use a threshold of 10). The gene has 8 curated benign missense variants. Gene score misZ: 0.16259 (below the threshold of 3.09). Trascript score misZ: -0.035144 (below the threshold of 3.09). GenCC associations: The gene is linked to Leydig cell hypoplasia, type 1, familial male-limited precocious puberty.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.96
• PP5: Variant 2-48688679-G-A is Pathogenic according to our data. Variant chr2-48688679-G-A is described in ClinVar as Pathogenic. ClinVar VariationId is 14397.Status of the report is no_assertion_criteria_provided, 0 stars.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_000233.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	LHCGR	NM_000233.4	MANE Select	c.1118C>T	p.Ala373Val	missense	Exon 11 of 11	NP_000224.2
	STON1-GTF2A1L	NM_001198593.2		c.3441+16999G>A		intron	N/A	NP_001185522.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	LHCGR	ENST00000294954.12	TSL:1 MANE Select	c.1118C>T	p.Ala373Val	missense	Exon 11 of 11	ENSP00000294954.6
	ENSG00000279956	ENST00000602369.3	TSL:5	n.*220+5545C>T		intron	N/A	ENSP00000473498.1
	LHCGR	ENST00000405626.5	TSL:5	c.1037C>T	p.Ala346Val	missense	Exon 10 of 10	ENSP00000386033.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 32

Alfa AF: 0.00 Hom.: 0

ClinVar

Significance: Likely pathogenic

Submissions summary: Pathogenic:2

Revision: criteria provided, single submitter

Submissions by phenotype

Gonadotropin-independent familial sexual precocity Pathogenic:2

Oct 09, 2025

Molecular Genetics and NGS Laboratory, Hospital Fundacion Valle Del Lili

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Currently, this variant is classified in databases such as Varsome and Franklin-Genoox as a variant of uncertain clinical significance (VUS). However, we propose its clinical reclassification as likely pathogenic, based on the personal and family history of our patient. 5-year-old patient with a history of serum hormone levels compatible with noncentral precocious puberty, generalized muscle mass gain, generalized hypertrichosis, early appearance of pubic hair, with poor testicular development, advanced bone age according to carpogram studies, 46,XY karyotype, no pituitary or adrenal pathology or identified tumor lesions, negative tumor markers, there is no significant family history, with a variant identified in heterozygosity in the LHCGR gene: c.1118C>T p.(Ala373Val), located in exon 11, meeting ACMG criteria for probably pathogenic classification: PM2, PP2, PP3, PP4, PP5. Segregation analysis in the parents could not be performed; therefore, the inheritance pattern of the variant remains undetermined. Nevertheless, the clinical and molecular findings support a diagnosis of a male-limited precocious puberty disorder in this patient. Male-limited precocious puberty disorder associated with the LHCGR has been described. Notably, the same variant has already been reported in a patient with onset of puberty at the age of 5 years, characterized by accelerated growth, enlargement of genitalia, pubarche, and serum hormone levels compatible with noncentral precocious puberty (DOI: 10.1210/jcem.83.2.4579).

Feb 01, 1998

OMIM

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.39
BayesDel_addAF	Pathogenic	0.46	D
BayesDel_noAF	Pathogenic	0.42
CADD	Pathogenic	28
DANN	Pathogenic	1.0
DEOGEN2	Uncertain	0.72	D
Eigen	Pathogenic	1.0
Eigen_PC	Pathogenic	0.94
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Pathogenic	0.99	D
M_CAP	Uncertain	0.26	D
MetaRNN	Pathogenic	0.96	D
MetaSVM	Pathogenic	0.98	D
MutationAssessor	Pathogenic	3.4	M
PhyloP100		10
PrimateAI	Uncertain	0.68	T
PROVEAN	Uncertain	-3.4	D
REVEL	Pathogenic	0.91
Sift	Uncertain	0.0010	D
Sift4G	Pathogenic	0.0010	D
Polyphen		1.0	D
Vest4		0.86
MutPred		0.84		Loss of helix (P = 0.1299)
MVP		0.98
MPC		0.46
ClinPred		1.0	D
GERP RS		5.7
Varity_R		0.94
gMVP		0.87
Mutation Taster		=3/97	disease causing (ClinVar)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.0		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs121912528; hg19: chr2-48915818;