ClinVar Miner

Submissions for variant NM_000497.4(CYP11B1):c.954G>A (p.Thr318=)

dbSNP: rs753774484
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Total submissions: 6
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Athena Diagnostics RCV000516213 SCV000613046 likely pathogenic not provided 2016-12-01 criteria provided, single submitter clinical testing
Invitae RCV000516213 SCV001581360 pathogenic not provided 2023-12-09 criteria provided, single submitter clinical testing This sequence change affects codon 318 of the CYP11B1 mRNA. It is a 'silent' change, meaning that it does not change the encoded amino acid sequence of the CYP11B1 protein. This variant also falls at the last nucleotide of exon 5, which is part of the consensus splice site for this exon. This variant is not present in population databases (gnomAD no frequency). This variant has been observed in individuals with adrenal hyperplasia (PMID: 26956189, 29858860, 31006099). ClinVar contains an entry for this variant (Variation ID: 447228). Variants that disrupt the consensus splice site are a relatively common cause of aberrant splicing (PMID: 17576681, 9536098). 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.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV003387864 SCV004099943 pathogenic Congenital adrenal hyperplasia 2023-09-18 criteria provided, single submitter clinical testing Variant summary: CYP11B1 c.954G>A (p.Thr318Thr) alters a non-conserved nucleotide located close to a canonical splice site and therefore could affect mRNA splicing, leading to a significantly altered protein sequence. 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 was absent in 251312 control chromosomes (gnomAD). c.954G>A has been reported in the literature in multiple homozygous individuals affected with 11-beta-hydroxylase deficiency (example: Yildiz_2021). These data indicate that the variant is very likely to be associated with disease. The following publication has been ascertained in the context of this evaluation (PMID: 33830237). Three submitters have cited clinical-significance assessments for this variant to ClinVar after 2014. All submitters classified the variant as pathogenic/likely pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic.
Baylor Genetics RCV000667365 SCV004215344 likely pathogenic Deficiency of steroid 11-beta-monooxygenase 2023-08-12 criteria provided, single submitter clinical testing
OMIM RCV000667365 SCV000021389 pathogenic Deficiency of steroid 11-beta-monooxygenase 2000-11-01 no assertion criteria provided literature only
Counsyl RCV000667365 SCV000791799 likely pathogenic Deficiency of steroid 11-beta-monooxygenase 2017-05-30 no assertion criteria provided clinical testing

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