Total submissions: 9
Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
---|---|---|---|---|---|---|---|---|
Athena Diagnostics Inc | 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, |
RCV000012938 | SCV000893710 | pathogenic | Classic congenital adrenal hyperplasia due to 21-hydroxylase deficiency | 2018-10-31 | criteria provided, single submitter | clinical testing | |
Myriad Genetics, |
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, |
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. |
Invitae | RCV000711390 | SCV002189414 | pathogenic | not provided | 2022-10-31 | 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). 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: 2072928, 28539365). For these reasons, this variant has been classified as Pathogenic. |
OMIM | RCV000012938 | SCV000033179 | pathogenic | Classic congenital adrenal hyperplasia due to 21-hydroxylase deficiency | 1997-07-01 | no assertion criteria provided | literature only | |
Gene |
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, |
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. |