ClinVar Miner

Submissions for variant NM_000497.4(CYP11B1):c.1269T>G (p.Tyr423Ter)

gnomAD frequency: 0.00001  dbSNP: rs267606755
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Total submissions: 7
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Counsyl RCV000001244 SCV000790308 likely pathogenic Deficiency of steroid 11-beta-monooxygenase 2017-03-15 criteria provided, single submitter clinical testing
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine RCV000001244 SCV000967661 pathogenic Deficiency of steroid 11-beta-monooxygenase 2018-06-27 criteria provided, single submitter clinical testing The p.Tyr423X variant in CYP11B1 has been reported in the compound heterozygote state in 1 individual with non-classic adrenal hyperplasia due to 11 beta-hydrox ylase deficiency (Joehrer 1997). This variant has been identified in 2/126704 Eu ropean chromosomes by the Genome Aggregation Database (gnomAD, http://gnomad.bro adinstitute.org; dbSNP rs267606755). This nonsense variant leads to a premature termination codon at position 423 which is predicted to lead to a truncated or a bsent protein. In summary, this variant meets criteria to be classified as patho genic for non-classic adrenal hyperplasia due to 11 beta-hydroxylase deficiency in an autosomal recessive manner based upon a case report, low frequency in con trols and predicted impact on protein. Criteria applied: PVS1, PM2, PM3_Supporti ng.
Invitae RCV001851530 SCV002226157 pathogenic not provided 2024-01-17 criteria provided, single submitter clinical testing This sequence change creates a premature translational stop signal (p.Tyr423*) in the CYP11B1 gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in CYP11B1 are known to be pathogenic (PMID: 8506298, 26476331). This variant is present in population databases (rs267606755, gnomAD 0.004%). This premature translational stop signal has been observed in individual(s) with non-classic 11-beta-hydroxylase deficiency (PMID: 9302260). ClinVar contains an entry for this variant (Variation ID: 1185). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. For these reasons, this variant has been classified as Pathogenic.
3billion RCV000001244 SCV002573252 pathogenic Deficiency of steroid 11-beta-monooxygenase 2022-09-01 criteria provided, single submitter clinical testing The variant is observed at an extremely low frequency in the gnomAD v2.1.1 dataset (total allele frequency: <0.001%). Stop-gained (nonsense) is predicted to result in a loss or disruption of normal protein function through nonsense-mediated decay (NMD) or protein truncation. Multiple pathogenic variants are reported downstream of the variant. The variant has been reported at least twice as pathogenic with clinical assertions and evidence for the classification (ClinVar ID: VCV000001185 / PMID: 9302260). Therefore, this variant is classified as Pathogenic according to the recommendation of ACMG/AMP guideline.
PreventionGenetics, part of Exact Sciences RCV003415613 SCV004116976 pathogenic CYP11B1-related disorder 2022-11-18 criteria provided, single submitter clinical testing The CYP11B1 c.1269T>G variant is predicted to result in premature protein termination (p.Tyr423*). This variant was reported in an individual with steroid-11 beta-hydroxylase deficiency (Joehrer et al. 1997. PubMed ID: 9302260). This variant is reported in 0.0015% of alleles in individuals of European (Non-Finnish) descent in gnomAD (http://gnomad.broadinstitute.org/variant/8-143956502-A-C). Nonsense variants in CYP11B1 are expected to be pathogenic. This variant is interpreted as pathogenic.
Baylor Genetics RCV000001244 SCV004215337 pathogenic Deficiency of steroid 11-beta-monooxygenase 2023-10-03 criteria provided, single submitter clinical testing
OMIM RCV000001244 SCV000021394 pathogenic Deficiency of steroid 11-beta-monooxygenase 1997-10-01 no assertion criteria provided literature only

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