ClinVar Miner

Submissions for variant NM_000497.4(CYP11B1):c.595+1G>A

gnomAD frequency: 0.00001  dbSNP: rs1264073726
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Total submissions: 6
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Counsyl RCV000667755 SCV000792254 likely pathogenic Deficiency of steroid 11-beta-monooxygenase 2017-06-13 criteria provided, single submitter clinical testing
Eurofins Ntd Llc (ga) RCV000732722 SCV000860703 pathogenic not provided 2018-03-30 criteria provided, single submitter clinical testing
Internal Medicine, University of Pretoria RCV000667755 SCV001192849 pathogenic Deficiency of steroid 11-beta-monooxygenase 2020-03-31 criteria provided, single submitter clinical testing Abolishes a canonical splice site in intron3/exon3.
Invitae RCV000732722 SCV001227308 pathogenic not provided 2023-09-21 criteria provided, single submitter clinical testing 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. ClinVar contains an entry for this variant (Variation ID: 552484). Disruption of this splice site has been observed in individuals with autosomal recessive adrenal hyperplasia and/or clinical features of autosomal recessive CYP11B1-related conditions (PMID: 28228528, 32561571, 33275286). This variant is present in population databases (no rsID available, gnomAD 0.004%). This sequence change affects a donor splice site in intron 3 of the CYP11B1 gene. It is expected to disrupt RNA splicing. Variants that disrupt the donor or acceptor splice site typically lead to a loss of protein function (PMID: 16199547), and loss-of-function variants in CYP11B1 are known to be pathogenic (PMID: 8506298, 26476331).
GeneDx RCV000732722 SCV002571511 uncertain significance not provided 2022-03-03 criteria provided, single submitter clinical testing Reported in patients with 11- beta hydroxylase deficiency who also harbor a missense variant in the CYP11B1 gene (Khattab et al., 2017; Karlekar et al., 2021); Identified in a patient with isolated hypertension and not other CYP11B1 variant were reported (Bao et al., 2020); Canonical splice site variant predicted to result in a null allele in a gene for which loss-of-function is a known mechanism of disease; This variant is associated with the following publications: (PMID: 32561571, 33275286, 28228528)
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV003230566 SCV003929028 likely pathogenic Congenital adrenal hyperplasia 2023-04-18 criteria provided, single submitter clinical testing Variant summary: CYP11B1 c.595+1G>A is located in a canonical splice-site and is predicted to affect mRNA splicing resulting in a significantly altered protein due to either exon skipping, shortening, or inclusion of intronic material. Several computational tools predict a significant impact on normal splicing: Four predict the variant abolishes a canonical 5' splicing donor site. However, these predictions have yet to be confirmed by functional studies. The variant allele was found at a frequency of 4e-06 in 249814 control chromosomes (gnomAD). c.595+1G>A has been reported in the literature in individuals affected with 11beta-hydroxylase deficiency (Karlekar_2021, Khattab_2017). These data indicate that the variant may be associated with disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Five ClinVar submitters have assessed the variant since 2014: one classified the variant as uncertain significance, one as likely pathogenic, and three as pathogenic. Based on the evidence outlined above, the variant was classified as likely pathogenic.

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