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

gnomAD frequency: 0.00001  dbSNP: rs1264073726

Total submissions: 7

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.
Baylor Genetics	RCV000667755	SCV005059291	pathogenic	Deficiency of steroid 11-beta-monooxygenase	2023-12-29	criteria provided, single submitter	clinical testing