Submissions for variant NM_000500.9(CYP21A2):c.844G>T (p.Val282Leu)

dbSNP: rs6471

Total submissions: 30

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	RCV000012934	SCV000245595	pathogenic	Classic congenital adrenal hyperplasia due to 21-hydroxylase deficiency	2014-10-17	criteria provided, single submitter	clinical testing	The p.Val282Leu variant (NM_000500.7 c.844G>T) (also referred to as p.Val281Leu in the literature) in CYP21A2 is a well-established pathogenic variant and has b een reported in numerous individuals with non-classical congenital adrenal hyper plasia (CAH) (Marino 2001, Ezquieta 2010, New 2013). This variant has also been reported in ClinVar (Variation ID#12151), as pathogenic. This variant has been i dentified in 2.0% (175/8588) of Ashkenazi Jewish chromosomes by the Genome Aggre gation Database (gnomAD, http://gnomad.broadinstitute.org; dbSNP rs6471), althou gh data at this locus may not be reliable due to high homology with a pseudogene . In vitro functional studies indicate that the p.Val282Leu variant may impact protein function (Tusie-Luna 1990, Barbaro 2015). In summary, this variant meets our criteria to be classified as pathogenic for non-classical CAH in an autosom al recessive manner based on observations in individuals with this disease and f unctional evidence. ACMG/AMP Criteria applied: PM3 (upgraded to strong based on multiple occurrences), PS3, PP5 (Richards 2015).
Ambry Genetics	RCV000210728	SCV000263011	pathogenic	Inborn genetic diseases	2022-04-20	criteria provided, single submitter	clinical testing	The c.844G>T (p.V282L) alteration is located in coding exon 7 of the CYP21A2 gene. This alteration results from a G to T substitution at nucleotide position 844, causing the valine (V) at amino acid position 282 to be replaced by a leucine (L). Based on data from gnomAD, the T allele has an overall frequency of 0.55% (1508/273420) total alleles studied. The highest observed frequency was 2.45% (223/9116) of Ashkenazi Jewish alleles. Data at this locus may not be reliable due to high homology with a pseudogene. This alteration, previously known as V281L, was detected in 94 patients with mild forms of 21-hydroxylase-deficient congenital adrenal hyperplasia (21-OHD CAH) and compound heterozygous with a severe mutation (Ezquieta, 2010). This alteration is typically associated with non-classic 21-OHD CAH when homozygous or compound heterozygous, even with a severe pathogenic variant (New, 2013; Livadas, 2015; Rodriguez 2017). This amino acid position is not well conserved in available vertebrate species. Functional analysis demonstrated that the p.V282L alteration reduces 21-hydroxylase activity by about 50% due to an increase in chain length resulting in relatively modest steric clashes in the I-helix of the protein (Haider, 2013; New, 2013). This alteration is predicted to be tolerated by in silico analysis. Based on the available evidence, this alteration is classified as pathogenic.
Knight Diagnostic Laboratories, Oregon Health and Sciences University	RCV000012934	SCV000494239	pathogenic	Classic congenital adrenal hyperplasia due to 21-hydroxylase deficiency	2016-06-27	criteria provided, single submitter	clinical testing	The well-known c.844G>T (p.Val282Leu) missense variant is frequently observed in individuals affected with non-classical congenital adrenal hyperplasia (GeneReviews: Nimkarn et al., 2016, , Eziquieta et al. 2010, Stikkelbroeck et al. 2003, Skordis et al. 2015, Ramazani et al. 2008). New et al. (2013) reported that 98% (n = 497) of individuals with Non-classical CAH harbored this variant and its frequency was very high in affected individuals from the Ashkenazi Jewish population. Although this variant is associated with non-classical CAH, individuals with classical CAH were also found to have this variant (New et al. 2013). Functional studies found that co-expression of this mutant protein and wild-type (WT) protein results in a dominant negative effect on the enzymatic activity of WT protein (Felix-Lopez et al. 2003). Other studies indicate reduced enzyme activity with the p.Val281Leu allele (Wu and Chung 1991, Haider et al. 2013). The variant is observed in the population databases at a frequency below expected for the carrier rate based on prevalence of disease (ExAC, 1000 Genomes, ESP). Reputable clinical labs have interpreted this variant as pathogenic (Partners HealthCare and Ambry Genetics). In summary, this mutation meets the criteria for a Pathogenic variant for Adrenal hyperplasia, congenital, due to 21 – hydroxylase deficiency. We have confirmed this finding in our laboratory using Sanger sequencing.
Fulgent Genetics, Fulgent Genetics	RCV000012934	SCV000611260	pathogenic	Classic congenital adrenal hyperplasia due to 21-hydroxylase deficiency	2017-05-18	criteria provided, single submitter	clinical testing
Institute Of Human Genetics Munich, Klinikum Rechts Der Isar, Tu München	RCV000012934	SCV000680185	pathogenic	Classic congenital adrenal hyperplasia due to 21-hydroxylase deficiency	2017-10-26	criteria provided, single submitter	clinical testing
Athena Diagnostics Inc	RCV000711385	SCV000841748	pathogenic	not provided	2023-02-28	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. This variant has been reported to associate with non-classic congenital adrenal hyperplasia (CAH). This variant is also referred to as p.Val281Leu 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. Expression of this variant results in reduced enzymatic activity compared to wild type (PMID: 2249999, 24953648).
Eurofins Ntd Llc (ga)	RCV000711385	SCV000854780	pathogenic	not provided	2018-04-23	criteria provided, single submitter	clinical testing
Mendelics	RCV000012934	SCV001137080	pathogenic	Classic congenital adrenal hyperplasia due to 21-hydroxylase deficiency	2019-05-28	criteria provided, single submitter	clinical testing
Myriad Genetics, Inc.	RCV000012934	SCV001193785	pathogenic	Classic congenital adrenal hyperplasia due to 21-hydroxylase deficiency	2019-12-26	criteria provided, single submitter	clinical testing	NM_000500.7(CYP21A2):c.844G>T(V282L, aka V281L) is classified as pathogenic in the context of congenital adrenal hyperplasia and is associated with the non-classic form of the disease. Sources cited for classification include the following: PMID 20661889, 14513879, 23359698, 20926536, 1644925, 1864962 and 2249999. Classification of NM_000500.7(CYP21A2):c.844G>T(V282L, aka V281L) 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	RCV000711385	SCV001449819	pathogenic	not provided	2015-04-30	criteria provided, single submitter	clinical testing
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV000711385	SCV001469965	pathogenic	not provided	2023-02-28	criteria provided, single submitter	clinical testing	The variant has been found in at least one symptomatic individual. Functional evidence suggests that this variant may impact protein function. The variant occurs in multiple cases with a lone recessive pathogenic/likely pathogenic variant in the same gene, and have phenotype known to be consistent with disease. Based on the available information, this variant is classified as pathogenic.
GeneDx	RCV000711385	SCV001805044	pathogenic	not provided	2021-02-18	criteria provided, single submitter	clinical testing	In silico analysis supports that this missense variant does not alter protein structure/function; This variant is associated with the following publications: (PMID: 10408786, 12038604, 10908170, 32714392, 31980526, 31586465, 28644547, 31605362, 31159521, 31344365, 31446012, 29525066, 30487145, 30656636, 29412390, 30609409, 25970792, 23359698, 3260007, 1864962, 26804566, 2249999, 27785393, 25481255, 25538881, 23359706, 21646730, 14513879, 20661889, 24953648, 30968594)
Revvity Omics, Revvity	RCV000711385	SCV002018115	pathogenic	not provided	2023-12-08	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV001804725	SCV002051107	pathogenic	Congenital adrenal hyperplasia	2021-12-14	criteria provided, single submitter	clinical testing	Variant summary: CYP21A2 c.844G>T (p.Val282Leu) results in a conservative amino acid change in the encoded protein sequence. Three of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 0.0053 in 242232 control chromosomes in the gnomAD database, including 2 homozygotes. c.844G>T has been reported in the literature in multiple individuals affected with Congenital Adrenal Hyperplasia (e.g. Barbat_1995, Marino_2020). These data indicate that the variant is very likely to be associated with disease. At least one publication reports experimental evidence evaluating an impact on protein function. The most pronounced variant effect results in 30%-50% of normal activity (White_2000). Twelve clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All laboratories classified the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic.
DASA	RCV000012934	SCV002061154	pathogenic	Classic congenital adrenal hyperplasia due to 21-hydroxylase deficiency	2022-01-05	criteria provided, single submitter	clinical testing	The c.844G>T;p.(Val282Leu) missense variant has been observed in affected individual(s) and ClinVar contains an entry for this variant (ClinVar ID: 12151; OMIM: 613815.0002; OMIM: 613815.0033; PMID: 20301350; 2788081; 3260007; 1496017; 7635470; 1985465; 9661649; 8081391;25356970; 20301350; 23359698) - PS4. Same amino acid change as a previously established pathogenic variant regardless of nucleotide change(ClinVar ID: 65610, PMID: 20301350) - PS1. The p.(Val282Leu) was detected in trans with a pathogenic variant (PMID: 23359698; 24953648; 25041270; 20301350; 28359061) - PM3_strong. and allele frequency is greater than expected for disorder -BS1. In summary, the currently available evidence indicates that the variant is pathogenic.
Invitae	RCV000711385	SCV002242900	pathogenic	not provided	2024-01-30	criteria provided, single submitter	clinical testing	This sequence change replaces valine, which is neutral and non-polar, with leucine, which is neutral and non-polar, at codon 282 of the CYP21A2 protein (p.Val282Leu). 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 primarily non-classic, and less frequently, classic salt-wasting or simple virilizing, congenital adrenal hyperplasia due to 21-hydroxylase deficiency (PMID: 1644925, 23359698, 24953648, 26804566, 31344365). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. It has also been observed to segregate with disease in related individuals. This variant is also known as V281L. ClinVar contains an entry for this variant (Variation ID: 12151). 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 with a negative predictive value of 80%. Experimental studies have shown that this missense change affects CYP21A2 function (PMID: 1864962, 2249999, 31344365). For these reasons, this variant has been classified as Pathogenic.
AiLife Diagnostics, AiLife Diagnostics	RCV000711385	SCV002502920	pathogenic	not provided	2022-03-24	criteria provided, single submitter	clinical testing
3billion	RCV000012934	SCV002521256	pathogenic	Classic congenital adrenal hyperplasia due to 21-hydroxylase deficiency	2022-05-22	criteria provided, single submitter	clinical testing	The variant is observed in the gnomAD v2.1.1 (https://gnomad.broadinstitute.org/) dataset at total allele frequency of 0.552%. 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. Functional studies provide strong evidence of the variant having a damaging effect on the gene or gene product (PMID:20661889, 21609351). In silico tool predictions suggest damaging effect of the variant on gene or gene product (REVEL: 0.31; 3Cnet: 0.78). Same nucleotide change resulting in same amino acid change has been previously reported as pathogenic/likely pathogenic with strong evidence (ClinVar ID: VCV000012151). The variant has been observed in multiple (>3) similarly affected unrelated individuals (PMID:20661889, 21609351). A different missense change at the same codon (p.Val282Gly) has been reported to be associated with CYP21A2 related disorder (PMID: 10720040). Therefore, this variant is classified as pathogenic according to the recommendation of ACMG/AMP guideline.
Victorian Clinical Genetics Services, Murdoch Childrens Research Institute	RCV000012934	SCV002769514	pathogenic	Classic congenital adrenal hyperplasia due to 21-hydroxylase deficiency	2021-05-06	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 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 valine to leucine (I) 0251 - This variant is heterozygous. (I) 0305 - Variant is present in gnomAD (v3) >=0.01 and <0.03 for a recessive condition (1630 heterozygotes, 4 homozygotes). (I) 0309 - An alternative amino acid change at the same position has been observed in gnomAD (v2) (3 heterozygotes, 0 homozygotes). (I) 0502 - Missense variant with conflicting in silico predictions and uninformative conservation. (I) 0600 - Variant is located in the annotated p450 domain (PDB). (I) 0801 - This variant has strong previous evidence of pathogenicity in unrelated individuals. This variant has been found in more than 500 patients, majority of whom presented with non-classical congenital adrenal hyperplasia (ClinVar; PMID: 23359698). (SP) 1208 - Inheritance information for this variant is not currently available in this individual. (I) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign
Lifecell International Pvt. Ltd	RCV000012934	SCV003852661	likely pathogenic	Classic congenital adrenal hyperplasia due to 21-hydroxylase deficiency		criteria provided, single submitter	clinical testing	A Heterozygous Missense variant c.844G>T in Exon 7 of the CYP21A2 gene that results in the amino acid substitution p.Val282Leu was identified. The observed variant has a minor allele frequency of 0.00528/0% in gnomAD exomes and genomes, respectively. The severity of the impact of this variant on the protein is medium, based on the effect of the protein and REVEL score . Rare Exome Variant Ensemble Learner (REVEL) is an ensembl method for predicting the pathogenicity of missense variants based on a combination of scores from 13 individual tools: MutPred, FATHMM v2.3, VEST 3.0, PolyPhen-2, SIFT, PROVEAN, MutationAssessor, MutationTaster, LRT, GERP++, SiPhy, phyloP, and phastCons. The REVEL score for an individual missense variant can range from 0 to 1, with higher scores reflecting greater likelihood that the variant is disease-causing. ClinVar has also classified this variant as Pathogenic (Variant ID: 12151). Experimental studies have shown that this missense change affects CYP21A2 function (Karlsson L et al., 2019). This variant is frequently observed in individuals affected with non-classical congenital adrenal hyperplasia. Based on the above evidence this variant has been classified as Likely Pathogenic according to the ACMG guidelines.
PreventionGenetics, part of Exact Sciences	RCV003407320	SCV004114182	pathogenic	CYP21A2-related condition	2023-05-24	criteria provided, single submitter	clinical testing	The CYP21A2 c.844G>T variant is predicted to result in the amino acid substitution p.Val282Leu. This is a common deleterious variant, which likely originated from the pseudogene CYP21A1P via gene conversion. This variant is a mild allele associated with non-classic congenital adrenal hyperplasia (CAH) (also known as V281L; see for example at New et al. 2013. PubMed ID: 23359698; Finkielstain et al. 2011. PubMed ID: 20926536). This variant is interpreted as pathogenic.
OMIM	RCV000012934	SCV000033175	pathogenic	Classic congenital adrenal hyperplasia due to 21-hydroxylase deficiency	1998-07-01	no assertion criteria provided	literature only
OMIM	RCV000012935	SCV000033176	pathogenic	Adenoma, cortisol-producing	1998-07-01	no assertion criteria provided	literature only
OMIM	RCV000012936	SCV000033177	pathogenic	Carcinoma, adrenocortical, androgen-secreting	1998-07-01	no assertion criteria provided	literature only
GeneReviews	RCV000012934	SCV000086803	not provided	Classic congenital adrenal hyperplasia due to 21-hydroxylase deficiency		no assertion provided	literature only
Reproductive Health Research and Development, BGI Genomics	RCV000012934	SCV001142354	pathogenic	Classic congenital adrenal hyperplasia due to 21-hydroxylase deficiency	2020-01-06	no assertion criteria provided	curation	NM_000500.7:c.844G>T in the CYP21A2 gene has an allele frequency of 0.023 in Ashkenazi Jewish subpopulation in the gnomAD database. The p.Val282Leu variant (NM_000500.7 c.844G>T) (also referred to as p.Val281Leu in the literature) in CYP21A2 is a well-established pathogenic variant and has been reported in numerous individuals with congenital adrenal hyperplasia (CAH), in trans with another pathogenic variant (PMID: 21609351; 20661889; 23359698). In vitro functional studies indicate that the p.Val282Leu variant may impact protein function (PMID: 24953648). Taken together, we interprete this variant as Pathogenic/Likely pathogenic. ACMG/AMP Criteria applied: PM3_Strong; PS3; PP4.
Department of Pathology and Laboratory Medicine, Sinai Health System	RCV000711385	SCV001552008	pathogenic	not provided	2022-11-18	no assertion criteria provided	clinical testing	The CYP21A2 c.844G>T (p.Val282Leu) variant was identified in the literature at a frequency of 0.239 in 3005 patient chromosomes with congenital adrenal hyperplasia due to 21-hydroxylate deficiency (CAH), patients exhibited both CAH as well as non-classical CAH; the variant was also observed in 13 of 72 (1 homozygous) patients suspected of having CAH (freq:0.194), all patients carrying the variant were identified as having non-classical CAH or were heterozygous carriers for a variant implicated in CAH; the variant was also identified at a frequency of 0.18 in 228 patient chromosomes with classical and non-classical CAH in a Brazilian cohort; and this variant was observed in 35 of 74 patient chromosomes (9 homozygous) with CAH in another Brazilian cohort (New_2013_PMID:23359698, Kopacek_2018_PMID:29715434, Bachega_1998_PMID:9851787, Nan_2021_PMID:33809035). The variant was also identified in dbSNP (ID: rs6471), ClinVar (classified as pathogenic 18X by Oregon Health and Sciences University, Gulgent Genetics, Athena Diagnostics, Myriad Women's Health, Ambry Genetics, Karolinska University Hospital, GGL Genetic Diagnostics, Partners HealthCare Personalized Medicine, Mendelics, Quest Diagnostics, OMIM, GeneReviews, BGI Genomics, Leiden University Medical Center, GeneDX, and Klinikum rechts der Isar), and Cosmic (3 samples, tissue distribution: lung and thyroid) databases. The variant was identified in control databases in 1508 of 273420 chromosomes (2 homozygous) at a frequency of 0.005515, and was observed at the highest frequency in the Ashkenazi Jewish population in 223 of 9116 chromosomes (freq: 0.02446) (Genome Aggregation Database September 7, 2021, v2.1.1). The p.Val282 residue is conserved in mammals and computational analyses (MUT Assesor, PolyPhen-2, SIFT, MutationTaster, Revel, FATHMM, MetaLR, DANN) 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 (Splice AI exome) do not predict a deleterious effect on splicing. Functional studies have found that the p.Val282Leu variant results in a 20-50% reduction in enzymatic activity (Tusie-Luna_1990_PMID:2249999). In summary, based on the above information this variant meets our laboratory’s criteria to be classified as pathogenic.
Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)	RCV000711385	SCV001800488	pathogenic	not provided		no assertion criteria provided	clinical testing
Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	RCV000711385	SCV001957946	pathogenic	not provided		no assertion criteria provided	clinical testing
Zotz-Klimas Genetics Lab, MVZ Zotz Klimas	RCV000012934	SCV004041737	pathogenic	Classic congenital adrenal hyperplasia due to 21-hydroxylase deficiency	2023-10-09	no assertion criteria provided	clinical testing