ClinVar Miner

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

gnomAD frequency: 0.00530  dbSNP: rs6445
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Total submissions: 27
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Eurofins Ntd Llc (ga) 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 RCV000711371 SCV000841733 pathogenic not provided 2023-03-13 criteria provided, single submitter clinical testing Frequency data for this variant in the general population cannot be distinguished from that of the CYP21P pseudogene, and are therefore uninformative in assessment of variant pathogenicity (Genome Aggregation Database (gnomAD), Cambridge, MA (URL: http://gnomad.broadinstitute.org)). This variant is reported to associate with non-classic congenital adrenal hyperplasia (CAH). This variant is also referred to as p.Pro453Ser (P453S) in published literature. In multiple individuals, this variant has been seen in trans with other recessive pathogenic variants in CYP21A2, suggesting this variant is also pathogenic. Assessment of experimental evidence suggests this variant results in abnormal protein function. This variant results in reduced enzymatic activity (PMID: 24953648).
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).
Clinical Genetics and Genomics, Karolinska University Hospital RCV000711371 SCV001449847 pathogenic not provided 2016-05-19 criteria provided, single submitter clinical testing
Institute for Clinical Genetics, University Hospital TU Dresden, University Hospital TU Dresden RCV000711371 SCV002009127 pathogenic not provided 2021-11-03 criteria provided, single submitter clinical testing
Revvity Omics, Revvity RCV000711371 SCV002018116 pathogenic not provided 2023-08-04 criteria provided, single submitter clinical testing
Quest Diagnostics Nichols Institute San Juan Capistrano RCV000711371 SCV002047337 pathogenic not provided 2023-03-13 criteria provided, single submitter clinical testing The variant seen in patients with salt-wasting phenotype (PMID: 12788866 (2003)) and simple virilizing phenotype (PMID: 18381579 (2008)). Functional evidence suggests that this variant may impact protein function. The variant occurs in multiple cases with a lone recessive pathogenic/likely pathogenic variant in the same gene, and have phenotype known to be consistent with disease.
Invitae RCV000711371 SCV002126037 pathogenic not provided 2022-11-01 criteria provided, single submitter clinical testing This sequence change replaces proline, which is neutral and non-polar, with serine, which is neutral and polar, at codon 454 of the CYP21A2 protein (p.Pro454Ser). The frequency data for this variant in the population databases (gnomAD) is considered unreliable due to the presence of homologous sequence, such as pseudogenes or paralogs, in the genome. This missense change has been observed in individual(s) with clinical features of non-classic congenital adrenal hyperplasia due to 21-hydroxylase deficiency (PMID: 1406699, 10720040, 12222711, 12887291, 21444649, 21843885, 22270556, 23073904, 31333583, 32966723). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. This variant is also known as P453S. ClinVar contains an entry for this variant (Variation ID: 12159). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is not expected to disrupt CYP21A2 protein function. Experimental studies have shown that this missense change affects CYP21A2 function (PMID: 18381579, 24953648, 30968594). For these reasons, this variant has been classified as Pathogenic.
AiLife Diagnostics, AiLife Diagnostics RCV000711371 SCV002501425 pathogenic not provided 2021-06-02 criteria provided, single submitter clinical testing
Mendelics RCV000012943 SCV002519469 pathogenic Classic congenital adrenal hyperplasia due to 21-hydroxylase deficiency 2022-05-04 criteria provided, single submitter clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV000012943 SCV002556234 pathogenic Classic congenital adrenal hyperplasia due to 21-hydroxylase deficiency 2022-06-29 criteria provided, single submitter clinical testing Variant summary: CYP21A2 c.1360C>T (p.Pro454Ser) results in a non-conservative amino acid change in the encoded protein sequence. Four of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 0.0046 in 137706 control chromosomes in the gnomAD database, including 2 homozygotes. This frequency is not significantly higher than expected for a pathogenic variant in CYP21A2 causing Congenital Adrenal Hyperplasia/Non-Classic (0.0046 vs 0.032), allowing no conclusion about variant significance. c.1360C>T has been reported in the literature in multiple individuals affected with Congenital Adrenal Hyperplasia. These data indicate that the variant is very likely to be associated with disease. At least one publication reports experimental evidence evaluating an impact on protein function. The most pronounced variant effect results in 10%-<30% of normal activity (Helmberg_1992, Nikoshkov_1997, Soardi_2008). Ten clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All laboratories classified the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic.
3billion RCV000012943 SCV002572784 likely pathogenic Classic congenital adrenal hyperplasia due to 21-hydroxylase deficiency 2022-09-01 criteria provided, single submitter clinical testing It is observed in the gnomAD v2.1.1 ( https://gnomad.broadinstitute.org ) dataset at total allele frequency of 0.453%. Missense changes are a common disease-causing mechanism. In silico tool predictions suggest damaging effect of the variant on gene or gene product (REVEL: 0.45; 3Cnet: 0.88). Same nucleotide change resulting in same amino acid change has been previously reported as pathogenic/likely pathogenic with strong evidence (ClinVar ID: VCV000012159). Therefore, this variant is classified as Likely pathogenic according to the recommendation of ACMG/AMP guideline.
MGZ Medical Genetics Center RCV002288483 SCV002579439 pathogenic Congenital lipoid adrenal hyperplasia due to STAR deficency 2021-07-26 criteria provided, single submitter clinical testing
Victorian Clinical Genetics Services, Murdoch Childrens Research Institute RCV000012943 SCV002768107 pathogenic Classic congenital adrenal hyperplasia due to 21-hydroxylase deficiency 2021-05-06 criteria provided, single submitter clinical testing Based on the classification scheme VCGS_Germline_v1.3.4, this variant is classified as Pathogenic. Following criteria are met: 0102 - Loss of function is a known mechanism of disease in this gene and is associated with nonclassic type hyperandrogenism due to 21-hydroxylase deficiency (MIM#201910). (I) 0106 - This gene is associated with autosomal recessive disease. (I) 0200 - Variant is predicted to result in a missense amino acid change from proline to serine. (I) 0251 - This variant is heterozygous. (I) 0304 - Variant is present in gnomAD <0.01 for a recessive condition (v2: 757 heterozygotes, 2 homozygotes). (SP) 0504 - Same amino acid change has been observed in placental mammals. (SB) 0604 - Variant is not located in an established domain, motif, hotspot or informative constraint region. (I) 0801 - This variant has strong previous evidence of pathogenicity in unrelated individuals. It is regarded as definitely pathogenic by EMQN (PMID: 32616876) and is associated to the nonclassic type of hyperandrogenism due to 21-hydroxylase deficiency (ClinVar, LOVD, PMID: 31586465). (SP) 1208 - Inheritance information for this variant is not currently available in this individual. (I) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign
Baylor Genetics RCV000012943 SCV003835070 pathogenic Classic congenital adrenal hyperplasia due to 21-hydroxylase deficiency 2021-10-18 criteria provided, single submitter clinical testing
Intergen, Intergen Genetics and Rare Diseases Diagnosis Center RCV000012943 SCV004021289 pathogenic Classic congenital adrenal hyperplasia due to 21-hydroxylase deficiency 2023-07-26 criteria provided, single submitter clinical testing
PreventionGenetics, part of Exact Sciences RCV003924827 SCV004746571 pathogenic CYP21A2-related disorder 2023-12-16 criteria provided, single submitter clinical testing The CYP21A2 c.1360C>T variant is predicted to result in the amino acid substitution p.Pro454Ser. This variant is associated with autosomal recessive non-classic congenital adrenal hyperplasia (CAH) (also known as P453S; New et al. 2006. PubMed ID: 16912124; Nikoshkov et al. 1997. PubMed ID: 8989258; Soardi et al. 2008. PubMed ID: 18381579). This is a common deleterious variant, which likely originated from the pseudogene CYP21A1P via gene conversion. This variant is interpreted as pathogenic.
Institute of Human Genetics, University Hospital Muenster RCV003985261 SCV004801697 pathogenic See cases 2022-08-19 criteria provided, single submitter clinical testing ACMG categories: PS3,PS4,PM1,PP3,PP5
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 not provided Classic congenital adrenal hyperplasia due to 21-hydroxylase deficiency no assertion provided literature only
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.
Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen RCV000711371 SCV001740291 pathogenic not provided no assertion criteria provided clinical testing
Genome Diagnostics Laboratory, Amsterdam University Medical Center RCV000711371 SCV001808018 pathogenic not provided no assertion criteria provided clinical testing
Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+ RCV000711371 SCV001953135 pathogenic not provided no assertion criteria provided clinical testing
Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center RCV000711371 SCV001967148 pathogenic not provided no assertion criteria provided clinical testing

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