ClinVar Miner

Submissions for variant NM_000497.4(CYP11B1):c.346T>G (p.Trp116Gly)

gnomAD frequency: 0.00001  dbSNP: rs772733691
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Total submissions: 5
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Counsyl RCV000668604 SCV000793234 uncertain significance Deficiency of steroid 11-beta-monooxygenase 2017-08-07 criteria provided, single submitter clinical testing
Illumina Laboratory Services, Illumina RCV000668604 SCV000916226 uncertain significance Deficiency of steroid 11-beta-monooxygenase 2017-04-28 criteria provided, single submitter clinical testing The CYP11B1 c.346T>G (p.Trp116Gly) variant is a missense variant that has been reported in a compound heterozygous state with a second missense variant in one individual with classic CYP11B1 deficiency (Parajes et al. 2010). Control data are not available for the p.Trp116Gly variant, which is reported at a frequency of 0.00002 in the European (non-Finnish) population of the Exome Aggregation Consortium. However, this frequency is based on one allele only in an area of good sequence coverage, so the variant is presumed to be rare. The Trp116 residue is noted to be conserved in the CYP11 family of proteins and is located in a region of the protein known to control access to the active site of the enzyme. The p.Trp116Gly variant is thought to affect substrate recognition. Expression of the p.Trp116Gly variant in COS-7 cells demonstrated an absence of enzymatic activity (Parajes et al. 2010). Two additional known pathogenic variants affect residue Trp116, p.Trp116Ter and p.Trp116Cys. Based on the evidence, the p.Trp116Gly variant is classified as a variant of unknown significance but suspicious for pathogenicity for congenital adrenal hyperplasia. This variant was observed by ICSL as part of a predisposition screen in an ostensibly healthy population.
Illumina Laboratory Services, Illumina RCV001161915 SCV001323830 uncertain significance Glucocorticoid-remediable aldosteronism 2017-04-28 criteria provided, single submitter clinical testing This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). No publications were found based on this search. Allele frequency data from public databases did not allow this variant to be ruled in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance.
Labcorp Genetics (formerly Invitae), Labcorp RCV001868223 SCV002266320 likely pathogenic not provided 2021-06-11 criteria provided, single submitter clinical testing Experimental studies have shown that this variant affects CYP11B1 protein function (PMID: 20089618). This sequence change replaces tryptophan with glycine at codon 116 of the CYP11B1 protein (p.Trp116Gly). The tryptophan residue is highly conserved and there is a large physicochemical difference between tryptophan and glycine. This variant is present in population databases (rs772733691, ExAC 0.001%). This variant has been observed in individual(s) with adrenal hyperplasia (PMID: 20089618). ClinVar contains an entry for this variant (Variation ID: 553208). 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 CYP11B1 protein function. This variant disrupts the p.Trp116 amino acid residue in CYP11B1. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 15755848, 18204274, 28228528). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic.
Fulgent Genetics, Fulgent Genetics RCV005046879 SCV005675136 likely pathogenic Deficiency of steroid 11-beta-monooxygenase; Glucocorticoid-remediable aldosteronism 2024-03-05 criteria provided, single submitter clinical testing

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