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

gnomAD frequency: 0.00530  dbSNP: rs6445

Total submissions: 29

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	2024-10-30	criteria provided, single submitter	clinical testing	This variant is located in a genomic region of low or unreliable sequencing quality, and therefore estimations of its population frequency are uninformative in assessment of variant pathogenicity. In multiple individuals, this variant has been seen in trans with other recessive pathogenic variants in CYP21A2, suggesting this variant is also pathogenic. 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. Assessment of experimental evidence suggests this variant results in abnormal protein function. (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.
Labcorp Genetics (formerly Invitae), Labcorp	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, Medical Genetics	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
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
Laboratory of Medical Genetics, National & Kapodistrian University of Athens	RCV000012943	SCV005051735	pathogenic	Classic congenital adrenal hyperplasia due to 21-hydroxylase deficiency	2024-02-01	criteria provided, single submitter	curation
Clinical Genetics Laboratory, Skane University Hospital Lund	RCV000711371	SCV005196638	pathogenic	not provided	2022-05-27	criteria provided, single submitter	clinical testing
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
PreventionGenetics, part of Exact Sciences	RCV003924827	SCV004746571	pathogenic	CYP21A2-related disorder	2024-09-23	no assertion criteria provided	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.