ClinVar Miner

Submissions for variant NM_000233.4(LHCGR):c.1635C>A (p.Cys545Ter)

gnomAD frequency: 0.00001  dbSNP: rs121912523
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Total submissions: 4
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Clinical Molecular Genetics Laboratory, Johns Hopkins All Children's Hospital RCV000015469 SCV000692110 pathogenic Leydig cell agenesis 2018-01-03 criteria provided, single submitter clinical testing
Fulgent Genetics, Fulgent Genetics RCV002490374 SCV002795895 likely pathogenic Leydig cell agenesis; Gonadotropin-independent familial sexual precocity 2021-12-31 criteria provided, single submitter clinical testing
Labcorp Genetics (formerly Invitae), Labcorp RCV003546456 SCV004274822 pathogenic not provided 2023-12-30 criteria provided, single submitter clinical testing This sequence change creates a premature translational stop signal (p.Cys545*) in the LHCGR gene. While this is not anticipated to result in nonsense mediated decay, it is expected to disrupt the last 155 amino acid(s) of the LHCGR protein. The frequency data for this variant in the population databases is considered unreliable, as metrics indicate poor data quality at this position in the gnomAD database. This premature translational stop signal has been observed in individual(s) with Leydig cell hypoplasia (PMID: 7581384). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 14391). Algorithms developed to predict the effect of variants on protein structure and function are not available or were not evaluated for this variant. Experimental studies have shown that this premature translational stop signal affects LHCGR function (PMID: 7581384). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may create or strengthen a splice site. This variant disrupts a region of the LHCGR protein in which other variant(s) (p.Ser616Tyr) have been determined to be pathogenic (PMID: 26246498, 27016457; Invitae). This suggests that this is a clinically significant region of the protein, and that variants that disrupt it are likely to be disease-causing. For these reasons, this variant has been classified as Pathogenic.
OMIM RCV000015469 SCV000035734 pathogenic Leydig cell agenesis 1998-11-01 no assertion criteria provided literature only

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