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

gnomAD frequency: 0.00117  dbSNP: rs6475

Total submissions: 20

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	2023-08-22	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).
Eurofins Ntd Llc (ga)	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 Genetics, 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 and Genomics, 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	2023-08-22	criteria provided, single submitter	clinical testing	The CYP21A2 c.518T>A (p.Ile173Asn) variant (also known as I173N or I172N) has been reported in the published literature in individuals affected with the classic salt-wasting, simple virilizing, and non-classic forms of CAH (PMIDs: 3257825 (1988), 17042033 (2006), 21098686 (2011), 23359698 (2013), 31586465 (2020)). In addition, experimental studies indicate this variant is damaging to protein function (PMIDs: 2249999 (1990), 24667412 (2014), 24671123 (2014)). The frequency of this variant in the general population, 0.0016 (41/25010 chromosomes (Genome Aggregation Database, http://gnomad.broadinstitute.org)), is consistent with pathogenicity. Based on the available information, this variant is classified as pathogenic.
Revvity Omics, Revvity	RCV000711382	SCV002018112	pathogenic	not provided	2023-03-20	criteria provided, single submitter	clinical testing
3billion	RCV000012933	SCV002059027	pathogenic	Classic congenital adrenal hyperplasia due to 21-hydroxylase deficiency	2022-01-03	criteria provided, single submitter	clinical testing	Same nucleotide change resulting in same amino acid change has been previously reported as pathogenic/likely pathogenic with strong evidence (ClinVar ID: VCV000012150, PMID:3257825, PS1_S). Functional studies provide strong evidence of the variant having a damaging effect on the gene or gene product (PMID: 24671123, PS3_S). In silico tool predictions suggest damaging effect of the variant on gene or gene product (REVEL: 0.766, PP3_P). A missense variant is a common mechanism associated with Hyperandrogenism (PP2_P). It is observed at an extremely low frequency in the gnomAD v2.1.1 dataset (total allele frequency: 0.000577, PM2_M). Therefore, this variant is classified as pathogenic according to the recommendation of ACMG/AMP guideline.
Provincial Medical Genetics Program of British Columbia, University of British Columbia	RCV000012933	SCV002320854	pathogenic	Classic congenital adrenal hyperplasia due to 21-hydroxylase deficiency	2022-01-01	criteria provided, single submitter	clinical testing
Victorian Clinical Genetics Services, Murdoch Childrens Research Institute	RCV000012933	SCV002767610	pathogenic	Classic congenital adrenal hyperplasia due to 21-hydroxylase deficiency	2020-10-15	criteria provided, single submitter	clinical testing	Based on the classification scheme VCGS_Germline_v1.3.2, 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. (I) 0106 - This gene is associated with autosomal recessive disease. (I) 0200 - Variant is predicted to result in a missense amino acid change from isoleucine to asparagine. (I) 0251 - This variant is heterozygous. (I) 0304 - Variant is present in gnomAD (v3) <0.01 for a recessive condition (166 heterozygotes, 0 homozygotes). (SP) 0502 - Missense variant with conflicting in silico predictions and uninformative conservation. (I) 0600 - Variant is located in the annotated cytochrome P450 domain (NCBI, PDB). (I) 0705 - No comparable missense variants have previous evidence for pathogenicity. (I) 0801 - This variant has strong previous evidence of pathogenicity in unrelated individuals. The variant has previously been reported in many patients with congenital adrenal hyperplasia (ClinVar, HGMD, PMID: 3257825, PMID: 31586465). (SP) 1206 - This variant has been shown to be paternally inherited (18G00267). (I) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign
Invitae	RCV000711382	SCV003252584	pathogenic	not provided	2022-10-31	criteria provided, single submitter	clinical testing	This sequence change replaces isoleucine, which is neutral and non-polar, with asparagine, which is neutral and polar, at codon 173 of the CYP21A2 protein (p.Ile173Asn). 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: 3257825, 8698338, 23359698, 26804566, 30968594). 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 I172N. ClinVar contains an entry for this variant (Variation ID: 12150). 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 expected to disrupt CYP21A2 protein function. Experimental studies have shown that this missense change affects CYP21A2 function (PMID: 2249999, 30968594). For these reasons, this variant has been classified as Pathogenic.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV003226157	SCV003922699	pathogenic	Congenital adrenal hyperplasia	2023-03-15	criteria provided, single submitter	clinical testing	Variant summary: CYP21A2 c.518T>A (p.Ile173Asn, aka. I172N) results in a non-conservative amino acid change in the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 0.00048 in 249434 control chromosomes (gnomAD). c.518T>A has been reported in the literature in numerous homozygous and compound heterozygous individuals affected with the classic salt-wasting, simple virilizing, and non-classic forms of Congenital Adrenal Hyperplasia (see e.g. Amor_1988, Dolzan_2005, Simonetti_2018, Xu_2019). These data indicate that the variant is very likely to be associated with disease. Publications also reported experimental evidence evaluating an impact on protein function, and demonstrated severely reduced enzyme activity (e.g. Tusie-Luna_1990, Chiou_1990, Xu_2019). 13 clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after, and all laboratories classified the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic.
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	not provided	Classic congenital adrenal hyperplasia due to 21-hydroxylase deficiency		no assertion provided	literature only
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).
Zotz-Klimas Genetics Lab, MVZ Zotz Klimas	RCV000012933	SCV004099489	pathogenic	Classic congenital adrenal hyperplasia due to 21-hydroxylase deficiency	2023-10-30	no assertion criteria provided	clinical testing