Submissions for variant NM_000500.9(CYP21A2):c.92C>T (p.Pro31Leu)

gnomAD frequency: 0.00055  dbSNP: rs9378251

Total submissions: 16

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Athena Diagnostics	RCV000711390	SCV000841753	pathogenic	not provided	2023-03-28	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)). 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 has been reported to associate with non-classic congenital adrenal hyperplasia (CAH). In some published literature, this variant is referred to as Pro30Leu or *8. Assessment of experimental evidence suggests this variant results in abnormal protein function. Studies have shown this variant significantly reduces enzymatic activity (PMID: 20080860, 23927611, 24953648, 28539365).
Fulgent Genetics, Fulgent Genetics	RCV000012938	SCV000893710	pathogenic	Classic congenital adrenal hyperplasia due to 21-hydroxylase deficiency	2018-10-31	criteria provided, single submitter	clinical testing
Myriad Genetics, Inc.	RCV000012938	SCV001194148	pathogenic	Classic congenital adrenal hyperplasia due to 21-hydroxylase deficiency	2019-12-17	criteria provided, single submitter	clinical testing	NM_000500.7(CYP21A2):c.92C>T(P31L) is classified as pathogenic in the context of congenital adrenal hyperplasia, CYP21A2-related and is associated with the non-classic form of disease. Sources cited for classification include the following: PMID 23142378, 16427797, 23359698, 1644925, 2072928 and 9215318. Classification of NM_000500.7(CYP21A2):c.92C>T(P31L) is based on the following criteria: This is a well-established pathogenic variant in the literature that has been observed more frequently in patients with clinical diagnoses than in healthy populations. Please note: this variant was assessed in the context of healthy population screening.
Clinical Genetics and Genomics, Karolinska University Hospital	RCV000711390	SCV001449882	pathogenic	not provided	2017-02-08	criteria provided, single submitter	clinical testing
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV000711390	SCV002046435	pathogenic	not provided	2023-03-28	criteria provided, single submitter	clinical testing	In the published literature, this variant has been reported in a non-classic phenotype of congenital adrenal hyperplasia (CAH) (PMID: 2072928 (1991)). It has also been seen in many affected individuals with either a salt-wasting or simple virilizing phenotype as a result of being carried in combination with different pathogenic variants (PMIDs: 22629504 (2012), 26425475 (2015), and 27041116 (2016)). Functional studies have shown this variant significantly reduces enzymatic activity (PMIDs: 20080860 (2010), 23927611 (2014), 24953648 (2015), and 28539365 (2017)). The variant under the control of the CYP21A2 gene promoter has been reported to cause a less severe phenotype than under the control of the CYP21A pseudogene promoter (PMID: 15670187 (2005)). The frequency of this variant in the general population, 0.00059 (14/23690 chromosomes (Genome Aggregation Database, http://gnomad.broadinstitute.org)), is uninformative in the assessment of its pathogenicity. Analysis of this variant using bioinformatics tools for the prediction of the effect of amino acid changes on protein structure and function yielded conflicting predictions that this variant is deleterious or benign. Based on the available information, this variant is classified as pathogenic.
Labcorp Genetics (formerly Invitae), Labcorp	RCV000711390	SCV002189414	pathogenic	not provided	2024-10-07	criteria provided, single submitter	clinical testing	This sequence change replaces proline, which is neutral and non-polar, with leucine, which is neutral and non-polar, at codon 31 of the CYP21A2 protein (p.Pro31Leu). 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 classic salt-wasting, simple virilizing, and non-classic congenital adrenal hyperplasia due to 21-hydroxylase deficiency (PMID: 2072928, 23142378, 23359698, 26804566, 31446012). 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 P30L. ClinVar contains an entry for this variant (Variation ID: 12153). Invitae Evidence Modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) indicates that this missense variant is not expected to disrupt CYP21A2 protein function with a negative predictive value of 80%. Experimental studies have shown that this missense change affects CYP21A2 function (PMID: 2072928, 28539365). For these reasons, this variant has been classified as Pathogenic.
Victorian Clinical Genetics Services, Murdoch Childrens Research Institute	RCV000012938	SCV005086586	pathogenic	Classic congenital adrenal hyperplasia due to 21-hydroxylase deficiency	2023-07-16	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 congenital adrenal hyperplasia due to 21-hydroxylase deficiency (MIM#201910) and hyperandrogenism nonclassic type 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 leucine. (I) 0251 - This variant is heterozygous (according to Fulgent Genetics report). (I) 0304 - Variant is present in gnomAD <0.01 for a recessive condition (v3: 77 heterozygotes, 1 homozygote). (SP) 0604 - Variant is not located in an established domain, motif, hotspot or informative constraint region. (I) 0801 - This variant has very strong previous evidence of pathogenicity in unrelated individuals. It has been detected in multiple patients (ClinVar, PMIDs: 35079965, 26804566). (SP) 1002 - This variant has moderate functional evidence supporting abnormal protein function. It has been shown to cause 30-60% loss of 21-hydroxylase enzymatic activity (PMID: 26804566). (SP) 1208 - Inheritance information for this variant is not currently available in this individual. (I) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign
Clinical Genetics Laboratory, Skane University Hospital Lund	RCV000711390	SCV005197681	pathogenic	not provided	2022-08-18	criteria provided, single submitter	clinical testing
Pittsburgh Clinical Genomics Laboratory, University of Pittsburgh Medical Center	RCV000012938	SCV005397328	pathogenic	Classic congenital adrenal hyperplasia due to 21-hydroxylase deficiency	2023-06-28	criteria provided, single submitter	clinical testing	This sequence variant is a single nucleotide substitution (C>T) at position 92 of the coding sequence of the CYP21A2 gene that results in a proline to leucine amino acid change at residue 31 of the cytochrome P450 family 21 subfamily A member 2 protein. This is a previously reported variant (ClinVar 12153) that has been observed in homozygous, hemizygous, and compound heterozygous individuals affected by non-classical, simple virilizing, or salt wasting forms of congenital adrel hyperplasia due to 21-hydroxylase deficiency (PMID: 23142378, 23359698, 26804566, 31446012). This variant is present in 43 of 271488 alleles (0.0158%) in the gnomAD population dataset. Multiple bioinformatic tools predict that this proline to leucine amino acid change would be damaging, and the proline residue at this position is highly conserved across the vertebrate species examined. Studies examining the functiol consequence of this variant found that this variant significantly reduces CYP21A2's catalytic ability (PMID: 2072928, 28539365). Based upon the evidence, we consider this to be a pathogenic variant. ACMG Criteria: PP3, PS3, PS4
Juno Genomics, Hangzhou Juno Genomics, Inc	RCV000012938	SCV005416957	pathogenic	Classic congenital adrenal hyperplasia due to 21-hydroxylase deficiency		criteria provided, single submitter	clinical testing	PM2_Supporting+PM5_Supporting+PM3_VeryStrong+PP4+PS3_Moderate
Genomic Medicine Center of Excellence, King Faisal Specialist Hospital and Research Centre	RCV000012938	SCV005421020	pathogenic	Classic congenital adrenal hyperplasia due to 21-hydroxylase deficiency	2024-12-10	criteria provided, single submitter	clinical testing	PS3, PM1, PM2, PM5, PP5, BP4
3billion	RCV000012938	SCV005906071	likely pathogenic	Classic congenital adrenal hyperplasia due to 21-hydroxylase deficiency	2023-10-28	criteria provided, single submitter	clinical testing	The variant is observed at an extremely low frequency in the gnomAD v2.1.1 dataset (total allele frequency: 0.016%). However, 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. Predicted Consequence/Location: Missense variant Same nucleotide change resulting in same amino acid change has been previously reported as pathogenic/likely pathogenic with strong evidence (ClinVar ID: VCV000012153 /PMID: 2072928). Different missense changes at the same codon (p.Pro31Gln, p.Pro31Ser) have been reported as pathogenic/likely pathogenic with strong evidence (ClinVar ID: VCV000988330, VCV002573056 /PMID: 10198222). Therefore, this variant is classified as Likely pathogenic according to the recommendation of ACMG/AMP guideline.
Department of Pathology and Laboratory Medicine, Sinai Health System	RCV000012938	SCV005915407	pathogenic	Classic congenital adrenal hyperplasia due to 21-hydroxylase deficiency	2023-04-22	criteria provided, single submitter	research
OMIM	RCV000012938	SCV000033179	pathogenic	Classic congenital adrenal hyperplasia due to 21-hydroxylase deficiency	1997-07-01	no assertion criteria provided	literature only
GeneReviews	RCV000012938	SCV000086805	not provided	Classic congenital adrenal hyperplasia due to 21-hydroxylase deficiency		no assertion provided	literature only
Foundation for Research in Genetics and Endocrinology, FRIGE's Institute of Human Genetics	RCV000012938	SCV000590901	pathogenic	Classic congenital adrenal hyperplasia due to 21-hydroxylase deficiency	2017-07-28	no assertion criteria provided	clinical testing	This variant has been reported in 1000 genomes database, dbSNP(rs9378251) and HGMD. The in silico prediction of this variant is disease-causing by MutationTaster.