ClinVar Miner

Submissions for variant NM_000500.9(CYP21A2):c.518T>A (p.Ile173Asn) (rs6475)

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Total submissions: 13
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Ambry Genetics RCV000622562 SCV000740722 pathogenic Inborn genetic diseases 2014-09-07 criteria provided, single submitter clinical testing
Genomic Research Center,Shahid Beheshti University of Medical Sciences RCV000012933 SCV000784270 pathogenic Classic congenital adrenal hyperplasia due to 21-hydroxylase deficiency 2018-03-05 criteria provided, single submitter clinical testing
Genomic Research Center,Shahid Beheshti University of Medical Sciences RCV000012933 SCV000784271 pathogenic Classic congenital adrenal hyperplasia due to 21-hydroxylase deficiency 2018-03-05 criteria provided, single submitter clinical testing
Athena Diagnostics Inc RCV000711382 SCV000841745 pathogenic not provided 2021-04-19 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. This variant is also referred to as p.Ile172Asn 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. Experiments demonstrate this variant results in dramatically reduced enzymatic activity (PMID: 2249999, 24667412, 24671123). Computational tools predict that this variant is damaging.
EGL Genetic Diagnostics, Eurofins Clinical Diagnostics RCV000711382 SCV000854779 pathogenic not provided 2018-07-20 criteria provided, single submitter clinical testing
Equipe Genetique des Anomalies du Developpement, Université de Bourgogne RCV000012933 SCV000883113 pathogenic Classic congenital adrenal hyperplasia due to 21-hydroxylase deficiency 2018-11-21 criteria provided, single submitter clinical testing
Fulgent Genetics,Fulgent Genetics RCV000012933 SCV000893712 pathogenic Classic congenital adrenal hyperplasia due to 21-hydroxylase deficiency 2018-10-31 criteria provided, single submitter clinical testing
Myriad Women's Health, Inc. RCV000012933 SCV001194146 pathogenic Classic congenital adrenal hyperplasia due to 21-hydroxylase deficiency 2019-12-20 criteria provided, single submitter clinical testing NM_000500.7(CYP21A2):c.518T>A(I173N) is classified as pathogenic in the context of congenital adrenal hyperplasia and is associated with the classic form of the disease. Sources cited for classification include the following: PMID 24667412, 21098686, 24671123, 23359698, 22270556, 19750867 and 3257825. Classification of NM_000500.7(CYP21A2):c.518T>A(I173N) 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 Karolinska University Hospital,Karolinska University Hospital RCV000711382 SCV001449827 pathogenic not provided 2015-11-09 criteria provided, single submitter clinical testing
Quest Diagnostics Nichols Institute San Juan Capistrano RCV000711382 SCV001469964 pathogenic not provided 2020-06-08 criteria provided, single submitter clinical testing The best available variant frequency is uninformative because it is below the disease allele frequency. Found in at least one patient with expected phenotype for this gene. Predicted to have a damaging effect on the protein. In multiple individuals, this variant has been seen with a single recessive pathogenic variant in the same gene, suggesting this variant may also be pathogenic. Assessment of experimental evidence suggests this variant results in abnormal protein function.
OMIM RCV000012933 SCV000033174 pathogenic Classic congenital adrenal hyperplasia due to 21-hydroxylase deficiency 1997-07-01 no assertion criteria provided literature only
GeneReviews RCV000012933 SCV000086799 pathologic Classic congenital adrenal hyperplasia due to 21-hydroxylase deficiency 2013-08-29 no assertion criteria provided curation Converted during submission to Pathogenic.
LifeCell International Pvt. Ltd RCV000012933 SCV001482475 pathogenic Classic congenital adrenal hyperplasia due to 21-hydroxylase deficiency no assertion criteria provided clinical testing This variant in exon 4 of the CYP21A2 gene results in the amino acid substitution from Isoleucine to Asparagine at codon 173 (p.Ile173Asn) with the sequence change of c.518T>A (NM_000500.7). This variant was observed in a proband with increased level of 17-OHP enzyme (86.9 nmol/L) which was screened for advanced newborn screening with confirmatory genetic reflex testing at lifecell diagnostics. The observed variant has a minor allele frequency of 0.000798722 and 0.0005771 in the 1000G database and gnomAD database respectively. The nucleotide is predicted conserved by GERP++ and PhyloP and the in-silico predictions by MutationTaster and SIFT are damaging. This variant lies in the p450 domain of CP21A_HUMAN protein (http://pfam.xfam.org/protein/P08686). This variant (also referred as Ile172Asn) has been previously reported for congenital adrenal hyperplasia (Amor et al., 1988;PMID: 3257825, Speiser et al., 1992;PMID: 1644925, New et al., 2013;PMID: 23359698). Experimental studies have shown that this variant results in abnormal protein function (Tusie-Luna et al., 1990;PMID: 2249999, Chiou et al., 1990;PMID: 2303461, Brønstad et al., 2014;PMID: 24671123).

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