Submissions for variant NM_000500.9(CYP21A2):c.1174G>A (p.Ala392Thr)

dbSNP: rs202242769

Total submissions: 15

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Soonchunhyang University Bucheon Hospital, Soonchunhyang University Medical Center	RCV000490344	SCV000267281	likely pathogenic	Classic congenital adrenal hyperplasia due to 21-hydroxylase deficiency	2016-03-18	criteria provided, single submitter	reference population
Fulgent Genetics, Fulgent Genetics	RCV000490344	SCV000893713	pathogenic	Classic congenital adrenal hyperplasia due to 21-hydroxylase deficiency	2018-10-31	criteria provided, single submitter	clinical testing
Mendelics	RCV000490344	SCV001137081	pathogenic	Classic congenital adrenal hyperplasia due to 21-hydroxylase deficiency	2022-05-20	criteria provided, single submitter	clinical testing
Institute of Medical Genetics and Genomics, Sir Ganga Ram Hospital	RCV000490344	SCV002496410	uncertain significance	Classic congenital adrenal hyperplasia due to 21-hydroxylase deficiency	2021-03-10	criteria provided, single submitter	clinical testing	Found in heterozygous state in a male 8 year old boy with precaucious puberty child. No other variant detected
3billion	RCV000490344	SCV002521518	uncertain significance	Classic congenital adrenal hyperplasia due to 21-hydroxylase deficiency	2022-05-22	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: 0.872%). In silico tool predictions suggest damaging effect of the variant on gene or gene product (REVEL: 0.39; 3Cnet: 0.86). Same nucleotide change resulting in same amino acid change has been previously reported to be associated with CYP21A2 related disorder (ClinVar ID: VCV000225335 / PMID: 17119906). However, the evidence of pathogenicity is insufficient at this time. Therefore, this variant is classified as uncertain significanceaccording to the recommendation of ACMG/AMP guideline.
Victorian Clinical Genetics Services, Murdoch Childrens Research Institute	RCV000490344	SCV002767645	likely pathogenic	Classic congenital adrenal hyperplasia due to 21-hydroxylase deficiency	2022-02-02	criteria provided, single submitter	clinical testing	Based on the classification scheme VCGS_Germline_v1.3.4, this variant is classified as Likely 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 alanine to threonine. (I) 0251 - This variant is heterozygous. (I) 0305 - Variant is present in gnomAD (v2) >=0.01 and <0.03 for a recessive condition (2320 heterozygotes, 0 homozygotes). (I) 0309 - An alternative amino acid change at the same position has been observed in gnomAD (v3) (7 heterozygotes, 0 homozygotes). (I) 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) 0704 - Another missense variant comparable to the one identified in this case has limited previous evidence for pathogenicity. The alternative change to a valine has been found in trans in an individual with congenital adrenal hyperplasia (PMID: 19531083). (SP) 0803 - This variant has limited previous evidence of pathogenicity in unrelated individuals. The variants has previously been reported as pathogenic (ClinVar, LOVD, VCGS, PMID: 17119906, 32616876) in patients with congenital adrenal hyperplasia, however it has also been classified as a VUS (ClinVar). (SP) 1002 - This variant has moderate functional evidence supporting abnormal protein function. Transfected COS-1 cells showed a significant reduction in enzyme activity and maximum velocity (PMID: 17119906). (SP) 1208 - Inheritance information for this variant is not currently available in this individual. (I) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign
Athena Diagnostics Inc	RCV001357310	SCV002771863	likely pathogenic	not provided	2023-04-21	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.Ala391Thr in published literature. This variant has been identified in at least one individual with non-classic congenital adrenal hyperplasia (CAH). Assessment of experimental evidence suggests this variant results in abnormal protein function. (PMID: 17119906)
Invitae	RCV001357310	SCV003245012	uncertain significance	not provided	2021-09-02	criteria provided, single submitter	clinical testing	This sequence change replaces alanine with threonine at codon 392 of the CYP21A2 protein (p.Ala392Thr). The alanine residue is highly conserved and there is a small physicochemical difference between alanine and threonine. The frequency data for this variant in the population databases is considered unreliable, as metrics indicate poor data quality at this position in the ExAC database. This missense change has been observed in individual(s) with simple virilizing and nonclassical congenital adrenal hyperplasia (PMID: 17119906, 21750395). In at least one individual the data is consistent with the variant being in trans (on the opposite chromosome) from a pathogenic variant. This variant is also known as A391T and c.2296G>A (p.Ala391Thr). ClinVar contains an entry for this variant (Variation ID: 225335). 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: 17119906). In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV003155127	SCV003844694	uncertain significance	not specified	2023-02-14	criteria provided, single submitter	clinical testing	Variant summary: CYP21A2 c.1174G>A (p.Ala392Thr) 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 0.0092 in 234892 control chromosomes (gnomAD). Due to high homology with the CYP21A1P pseudogene, allele frequency data from the general population is uninformative for the assessment of this variant. c.1174G>A has been reported in the literature in at least one compound heterozygous individual affected with Congenital Adrenal Hyperplasia (e.g. Robins_2007). These data do not allow any conclusion about variant significance. Transient expression in COS-1 cells have demonstrated the variant has 38.9% enzymatic activity for the conversion of 17-OHP and 22.9% activity for progesterone (Robins_2007). Eight ClinVar submitters have assessed the variant since 2014: three classified the variant as uncertain significance, three as likely pathogenic, and two as pathogenic. Based on the evidence outlined above, the variant was classified as VUS-possibly pathogenic.
Neuberg Supratech Reference Laboratories Pvt Ltd, Neuberg Centre for Genomic Medicine	RCV000490344	SCV004100553	likely pathogenic	Classic congenital adrenal hyperplasia due to 21-hydroxylase deficiency		criteria provided, single submitter	clinical testing	The missense variant p.A392T in CYP21A2 (NM_000500.9) has been reported in compound heterozygous state in a child with congenital adrenal hyperplasia with 21 hydroxylase deficiency (Robins et al,2007). It has been submitted to ClinVar with varying interpretations: Pathogenic/Likely Pathogenic/ Uncertain Significance. Although the variant is present at 0.9213% in gnomAD Exomes, it has the flag "Failed Random Forest" and may not represent the true population frequency. The p.A392T variant is novel (not in any individuals) in 1000 Genomes. The p.A392T missense variant is predicted to be damaging by both SIFT and PolyPhen2. The nucleotide c.1174 in CYP21A2 is predicted conserved by GERP++ and PhyloP across 100 vertebrates. For these reasons, this variant has been classified as Likely Pathogenic.In the absence of another reportable variant, the molecular diagnosis of 21 hydroxylase deficiency is not confirmed.
Center for Genomic Medicine, King Faisal Specialist Hospital and Research Center	RCV000490344	SCV004805560	uncertain significance	Classic congenital adrenal hyperplasia due to 21-hydroxylase deficiency	2024-03-25	criteria provided, single submitter	research
Department of Pathology and Laboratory Medicine, Sinai Health System	RCV001357310	SCV001552744	uncertain significance	not provided		no assertion criteria provided	clinical testing	The CYP21A2 p.Ala362Thr variant was identified as a compound heterozygous variant with a CYP21A2 p.V282L variant in a girl with congenital adrenal hyperplasia (CAH) due to 21-hydroxylase; compound heterozygousity was confirmed through genotyping of the parents (Robins_2007_PMID:17119906). Whole exome sequencing of 43 children with a diagnosis of familial glucocorticoid deficiency identified the p.A362T variant as a heterozygous variant in one patient; a second variant was not identified (Chan_2015_PMID:26300845). The variant was identified in dbSNP (ID: rs202242769), ClinVar (classified as pathogenic by Fulgent Genetics and as likely pathogenic by Soonchunhyang University Bucheon Hospital, Soonchunhyang University Medical Center) and LOVD 3.0 (classified as likely benign). The variant was identified in control databases in 2320 of 266040 chromosomes (0 homozygous) at a frequency of 0.00872 increasing the likelihood this could be a low frequency benign variant (Genome Aggregation Database March 6, 2019, v2.1.1). The variant was observed in the following populations: South Asian in 846 of 29396 chromosomes (freq: 0.02878), East Asian in 153 of 19106 chromosomes (freq: 0.008008), European (non-Finnish) in 929 of 119756 chromosomes (freq: 0.007757), Ashkenazi Jewish in 75 of 10030 chromosomes (freq: 0.007478), Other in 41 of 6796 chromosomes (freq: 0.006033), European (Finnish) in 125 of 23452 chromosomes (freq: 0.00533), Latino in 114 of 34736 chromosomes (freq: 0.003282), and African in 37 of 22768 chromosomes (freq: 0.001625). The p.Ala362 residue is conserved in mammals and computational analyses (PolyPhen-2, SIFT, AlignGVGD, BLOSUM, MutationTaster) provide inconsistent predictions regarding the impact to the protein; this information is not very predictive of pathogenicity. The variant occurs outside of the splicing consensus sequence and in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer) do not predict a difference in splicing. In summary, based on the above information the clinical significance of this variant cannot be determined with certainty at this time. This variant is classified as a variant of uncertain significance.
Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	RCV001357310	SCV001740033	pathogenic	not provided		no assertion criteria provided	clinical testing
Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)	RCV001357310	SCV001800107	pathogenic	not provided		no assertion criteria provided	clinical testing
Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	RCV001357310	SCV002038377	pathogenic	not provided		no assertion criteria provided	clinical testing