Submissions for variant NM_000233.4(LHCGR):c.1733A>G (p.Asp578Gly)

dbSNP: rs121912518

Total submissions: 6

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Athena Diagnostics	RCV000517056	SCV000614017	pathogenic	not provided	2024-11-01	criteria provided, single submitter	clinical testing	This variant has not been reported in large, multi-ethnic general populations. (http://gnomad.broadinstitute.org) This variant segregates with familial male precocious puberty 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). At least one other missense variant at this codon is considered to be pathogenic or likely pathogenic, suggesting this variant may also cause disease.
Fulgent Genetics, Fulgent Genetics	RCV000763499	SCV000894285	pathogenic	Leydig cell agenesis; Gonadotropin-independent familial sexual precocity	2018-10-31	criteria provided, single submitter	clinical testing
GeneDx	RCV000517056	SCV001812796	pathogenic	not provided	2024-12-10	criteria provided, single submitter	clinical testing	Published functional studies demonstrate that p.(D578G) is an activating variant (PMID: 21490077, 7692306); Male members of a knock-in mouse model demonstrated precocious puberty (PMID: 23861372); Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 7692306, 8943222, 9703386, 26040673, 7714085, 7527413, 8855841, 21490077, 7562970, 30283825, 23861372)
Labcorp Genetics (formerly Invitae), Labcorp	RCV000517056	SCV002218734	pathogenic	not provided	2024-10-17	criteria provided, single submitter	clinical testing	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). Invitae Evidence Modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) 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.
OMIM	RCV000015461	SCV000035726	pathogenic	Gonadotropin-independent familial sexual precocity	1998-07-01	no assertion criteria provided	literature only
Clinical Molecular Genetics Laboratory, Johns Hopkins All Children's Hospital	RCV000583503	SCV000692111	pathogenic	Precocious puberty in males	2012-11-09	no assertion criteria provided	clinical testing