ClinVar Miner

Submissions for variant NM_000500.9(CYP21A2):c.1360C>T (p.Pro454Ser) (rs6445)

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Total submissions: 8
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
EGL Genetic Diagnostics,Eurofins Clinical Diagnostics RCV000711371 SCV000224844 pathogenic not provided 2014-12-29 criteria provided, single submitter clinical testing
Knight Diagnostic Laboratories, Oregon Health and Sciences University RCV000012943 SCV000494248 pathogenic Classic congenital adrenal hyperplasia due to 21-hydroxylase deficiency 2016-07-18 criteria provided, single submitter clinical testing The c.1360C>T (p.Pro454Ser) missense variant in the CYP21A2 gene has been previously reported in multiple individuals affected with 21-OHD CAH and is associated with the non-classic form of this disorder (Owerbach et al., 1992; Vigliani and Buster, 2012; Skordis et al., 2015; Neocleous et al., 2014). This variant is present significantly more frequently in affected individuals than controls (OR = 18; 95%CI = 2.37-136), and is absent or reported at low frequency in the population databases (Exome Sequencing Project [ESP]; 1000 Genomes=0.6%; ExAC=0.88%). Furthermore, in vitro functional assays in multiple studies demonstrated that, compared to the wild-type enzyme, this variant had decreased activity on both the 17-OHP and progesterone substrates (Nikoshkov et al., 1997, Barbaro et al., 2015). Structural studies predict that Pro454 is positioned within a hydrophobic pocket, and that the p.Pro454Ser variant will disrupt the hydrophobicity of this region (Haider et al., 2013). In addition, Emory Genetics Laboratory has classified this variant as Pathogenic. Pathogenic variants in the CYP21A2 gene are the only known cause of 21-OHD CAH. Therefore, this collective evidence supports the classification of the c.1360C>T (p.Pro454Ser) as a Pathogenic variant for congenital adrenal hyperplasia. We have confirmed this finding in our laboratory using Sanger sequencing.
Athena Diagnostics Inc RCV000711371 SCV000841733 pathogenic not provided 2016-02-11 criteria provided, single submitter clinical testing
Fulgent Genetics,Fulgent Genetics RCV000012943 SCV000893714 pathogenic Classic congenital adrenal hyperplasia due to 21-hydroxylase deficiency 2018-10-31 criteria provided, single submitter clinical testing
UNC Molecular Genetics Laboratory,University of North Carolina at Chapel Hill RCV000012943 SCV001251458 pathogenic Classic congenital adrenal hyperplasia due to 21-hydroxylase deficiency criteria provided, single submitter research The CYP21A2 c.1360C>T (p.P454S) missense variant has been reported in individuals with nonclassical late-onset 21-hydroxylase deficiency (PMID: 1406699; 18381579; 1496017).
OMIM RCV000012943 SCV000033185 pathogenic Classic congenital adrenal hyperplasia due to 21-hydroxylase deficiency 2008-06-01 no assertion criteria provided literature only
GeneReviews RCV000012943 SCV000086792 pathologic Classic congenital adrenal hyperplasia due to 21-hydroxylase deficiency 2013-08-29 no assertion criteria provided curation Converted during submission to Pathogenic.
Reproductive Health Research and Development,BGI Genomics RCV000012943 SCV001142355 pathogenic Classic congenital adrenal hyperplasia due to 21-hydroxylase deficiency 2020-01-06 no assertion criteria provided curation NM_000500.7:c.1360C>T in the CYP21A2 gene has an allele frequency of 0.009 in European (non-Finnish) subpopulation in the gnomAD database. The c.1360C>T (p.Pro454Ser) missense variant in the CYP21A2 gene, also known as p.Pro453Ser in literatures, has been previously found in 46.2% of 13 unrelated NC-CAH patients, but only 7.7% and 3.6% of salt-wasting CAH patients and blood donors, respectively (PMID: 1406699). In vitro functional assays in multiple studies demonstrated that, compared to the wild-type enzyme, this variant had decreased activity on both the 17-OHP and progesterone substrates (PMID: 24953648). Pathogenic computational verdict because pathogenic predictions from DANN, EIGEN, FATHMM-MKL, M-CAP, MutationTaster and SIFT. Taken together, we interprete this variant as Pathogenic/Likely pathogenic. ACMG/AMP Criteria applied: PP3, PS4, PS3.

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