6-32040110-G-T

Variant names:

• chr6-32040110-G-T
• rs6471
• NM_000500.9:c.844G>T

Variant summary

Our verdict is Likely pathogenic. The variant received 7 ACMG points: 9P and 2B. PP2 PP5_Very_Strong BP4 BS2_Supporting

The NM_000500.9(CYP21A2):​c.844G>T​(p.Val282Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.005 in 1,595,168 control chromosomes in the GnomAD database, including 20 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★★). Another nucleotide change resulting in the same amino acid substitution has been previously reported as Uncertain significance in ClinVar.

• Frequency:
  • Genomes: 𝑓 0.011 (4 hom., cov: 32)
  • Exomes 𝑓: 0.0044 (16 hom.)
• Consequence: CYP21A2 NM_000500.9 missense
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:36 O:1
• Conservation: PhyloP100: 2.60
• Publications: 280 publications found

Genes affected

CYP21A2 (HGNC:2600): (cytochrome P450 family 21 subfamily A member 2) This gene encodes a member of the cytochrome P450 superfamily of enzymes. The cytochrome P450 proteins are monooxygenases which catalyze many reactions involved in drug metabolism and synthesis of cholesterol, steroids and other lipids. This protein localizes to the endoplasmic reticulum and hydroxylates steroids at the 21 position. Its activity is required for the synthesis of steroid hormones including cortisol and aldosterone. Mutations in this gene cause congenital adrenal hyperplasia. A related pseudogene is located near this gene; gene conversion events involving the functional gene and the pseudogene are thought to account for many cases of steroid 21-hydroxylase deficiency. Two transcript variants encoding different isoforms have been found for this gene. [provided by RefSeq, Jul 2008]

CYP21A2 Gene-Disease associations (from GenCC):

• classic congenital adrenal hyperplasia due to 21-hydroxylase deficiency

  Inheritance: AR Classification: DEFINITIVE, STRONG Submitted by: Myriad Women’s Health, Labcorp Genetics (formerly Invitae), Laboratory for Molecular Medicine
• classic congenital adrenal hyperplasia due to 21-hydroxylase deficiency, salt wasting form

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet
• classic congenital adrenal hyperplasia due to 21-hydroxylase deficiency, simple virilizing form

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Likely_pathogenic. The variant received 7 ACMG points.

• PP2: Missense variant in the gene, where a lot of missense mutations are associated with disease in ClinVar. The gene has 52 curated pathogenic missense variants (we use a threshold of 10). The gene has 5 curated benign missense variants. Trascript score misZ: 1.8021 (below the threshold of 3.09). GenCC associations: The gene is linked to classic congenital adrenal hyperplasia due to 21-hydroxylase deficiency, simple virilizing form, classic congenital adrenal hyperplasia due to 21-hydroxylase deficiency, classic congenital adrenal hyperplasia due to 21-hydroxylase deficiency, salt wasting form.
• PP5: Variant 6-32040110-G-T is Pathogenic according to our data. Variant chr6-32040110-G-T is described in ClinVar as Pathogenic/Likely_pathogenic. ClinVar VariationId is 12151.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP4: Computational evidence support a benign effect (MetaRNN=0.0096589625). . Strength limited to SUPPORTING due to the PP5.
• BS2: High Homozygotes in GnomAd4 at 4 AR geneVariant has number of homozygotes lower than other variant known as pathogenic in the gene, so the strength is limited to Supporting.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CYP21A2	NM_000500.9	c.844G>T	p.Val282Leu	missense_variant	Exon 7 of 10	ENST00000644719.2	NP_000491.4
CYP21A2	NM_001128590.4	c.754G>T	p.Val252Leu	missense_variant	Exon 6 of 9		NP_001122062.3
CYP21A2	NM_001368143.2	c.439G>T	p.Val147Leu	missense_variant	Exon 7 of 10		NP_001355072.1
CYP21A2	NM_001368144.2	c.439G>T	p.Val147Leu	missense_variant	Exon 6 of 9		NP_001355073.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CYP21A2	ENST00000644719.2	c.844G>T	p.Val282Leu	missense_variant	Exon 7 of 10		NM_000500.9	ENSP00000496625.1

Frequencies

GnomAD3 genomes AF: 0.0109 AC: 1638 AN: 150884 Hom.: 4 Cov.: 32

Gnomad AFR AF: 0.00485

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0276

Gnomad ASJ AF: 0.0723

Gnomad EAS AF: 0.00213

Gnomad SAS AF: 0.00124

Gnomad FIN AF: 0.00113

Gnomad MID AF: 0.0160

Gnomad NFE AF: 0.0104

Gnomad OTH AF: 0.0245

GnomAD2 exomes AF: 0.00528 AC: 1280 AN: 242232 AF XY: 0.00442

Gnomad AFR exome AF: 0.00295

Gnomad AMR exome AF: 0.0134

Gnomad ASJ exome AF: 0.0233

Gnomad EAS exome AF: 0.000932

Gnomad FIN exome AF: 0.000880

Gnomad NFE exome AF: 0.00447

Gnomad OTH exome AF: 0.00865

GnomAD4 exome AF: 0.00439 AC: 6337 AN: 1444170 Hom.: 16 Cov.: 38 AF XY: 0.00429 AC XY: 3082 AN XY: 718662

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.00297 AC: 99 AN: 33278

American (AMR) AF: 0.0149 AC: 661 AN: 44246

Ashkenazi Jewish (ASJ) AF: 0.0452 AC: 1126 AN: 24906

East Asian (EAS) AF: 0.000631 AC: 25 AN: 39634

South Asian (SAS) AF: 0.000905 AC: 78 AN: 86152

European-Finnish (FIN) AF: 0.00136 AC: 71 AN: 52258

Middle Eastern (MID) AF: 0.00959 AC: 54 AN: 5628

European-Non Finnish (NFE) AF: 0.00334 AC: 3669 AN: 1098614

Other (OTH) AF: 0.00932 AC: 554 AN: 59454

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome AF: 0.0109 AC: 1639 AN: 150998 Hom.: 4 Cov.: 32 AF XY: 0.00968 AC XY: 715 AN XY: 73886

⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.00486 AC: 201 AN: 41396

American (AMR) AF: 0.0276 AC: 415 AN: 15012

Ashkenazi Jewish (ASJ) AF: 0.0723 AC: 238 AN: 3290

East Asian (EAS) AF: 0.00214 AC: 11 AN: 5150

South Asian (SAS) AF: 0.00125 AC: 6 AN: 4816

European-Finnish (FIN) AF: 0.00113 AC: 12 AN: 10616

Middle Eastern (MID) AF: 0.0174 AC: 5 AN: 288

European-Non Finnish (NFE) AF: 0.0104 AC: 701 AN: 67460

Other (OTH) AF: 0.0242 AC: 50 AN: 2062

⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5. (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

Alfa AF: 0.00714 Hom.: 0

ExAC AF: 0.0103 AC: 1240

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:36 Other:1

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Classic congenital adrenal hyperplasia due to 21-hydroxylase deficiency Pathogenic:19 Other:1

Oct 09, 2023

Zotz-Klimas Genetics Lab, MVZ Zotz Klimas

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

-

Juno Genomics, Hangzhou Juno Genomics, Inc

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

PM3_VeryStrong+PS3 -

Jun 05, 2023

Newborn Screening Ontario, Children's Hospital of Eastern Ontario (CHEO)

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Dec 26, 2019

Myriad Genetics, Inc.

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: 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. -

Jan 05, 2022

DASA

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: 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. -

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Lifecell International Pvt. Ltd

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: 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. -

May 18, 2017

Fulgent Genetics, Fulgent Genetics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

May 28, 2019

Mendelics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

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GeneReviews

Significance: not provided

Review Status: no classification provided

Collection Method: literature only

- -

Feb 01, 2024

Laboratory of Medical Genetics, National & Kapodistrian University of Athens

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: curation

- -

Oct 26, 2017

Institute of Human Genetics Munich, TUM University Hospital

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Jan 22, 2024

3billion

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

It is observed in the gnomAD v2.1.1 (https://gnomad.broadinstitute.org) dataset (total allele frequency: 0.552% NA). Predicted Consequence/Location: Missense variant 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 [3Cnet: 0.83 (>=0.6, sensitivity 0.72 and precision 0.9)]. Same nucleotide change resulting in same amino acid change has been previously reported as pathogenic/likely pathogenic with strong evidence (ClinVar ID: VCV000012151 /PMID: 3260007 /3billion dataset). 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. -

Jul 16, 2023

Victorian Clinical Genetics Services, Murdoch Childrens Research Institute

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: 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 (MIM #201910) 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 (v2) >=0.01 and <0.03 for a recessive condition (1504 heterozygotes, 2 homozygotes). (I) 0309 - An alternative amino acid change at the same position has been observed in gnomAD (v2) (p.(Val282Met): 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 (NCBI). (I) 0801 - This variant has strong previous evidence of pathogenicity in unrelated individuals. This variant has been classified as pathogenic by multiple clinical laboratories and has been reported in more than 500 patients, the 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 -

Jul 01, 1998

OMIM

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

- -

Aug 15, 2024

Molecular Genetics and NGS Laboratory, Hospital Fundacion Valle Del Lili

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Combined evidence strength is Very Strong (score = 9): ClinVar classifies this variant as Pathogenic, 2 stars. backed by functional studies (PS3). Combined evidence strength is Very Strong (score = 9).Very Strong: Saphetor curators have classified this variant as Pathogenic.Supporting: LOVD classifies this variant as Pathogeni (PP5). Equivalent variant chr6:32040110 G>C (Val282Leu) is classified Pathogenic by UniProt Variants (PS1).UniProt protein CP21A_HUMAN Mutagen sequence annotations V > T: Decreased 21-hydroxylase activity. which qualifies as strong pathogenic (PM1). MetaRNN = 0.00966 is between 0.00692 and 0.108 = strong benign. Reducing to strength Supporting in view of the clinical evidence reported in PP5_Very Strong.We observed this variant in a 21-year-old patient with Turner syndrome and congenital adrenal hyperplasia. -

Mar 26, 2024

Genomic Medicine Center of Excellence, King Faisal Specialist Hospital and Research Centre

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Jun 27, 2016

Knight Diagnostic Laboratories, Oregon Health and Sciences University

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: 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. -

May 26, 2025

Institute of Human Genetics, University of Leipzig Medical Center

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Criteria applied: PM3_VSTR,PS1,PM1,PM5,PP4 -

Oct 17, 2014

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: 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). -

Jan 06, 2020

Reproductive Health Research and Development, BGI Genomics

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: 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. -

not provided Pathogenic:12

Apr 30, 2015

Clinical Genetics and Genomics, Karolinska University Hospital

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Sep 18, 2024

Athena Diagnostics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant is located in a genomic region of low or unreliable sequencing quality, and therefore estimations of its population frequency are uninformative in assessment of variant pathogenicity. (http://gnomad.broadinstitute.org) 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). -

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Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

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Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Feb 28, 2023

Quest Diagnostics Nichols Institute San Juan Capistrano

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: 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. -

Mar 24, 2022

AiLife Diagnostics, AiLife Diagnostics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Nov 18, 2022

Department of Pathology and Laboratory Medicine, Sinai Health System

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: 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. -

Apr 23, 2018

Eurofins Ntd Llc (ga)

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Jan 27, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: 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). Invitae Evidence Modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) 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. -

Apr 28, 2023

Clinical Genetics Laboratory, Skane University Hospital Lund

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Feb 18, 2021

GeneDx

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: 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) -

Dec 08, 2023

Revvity Omics, Revvity

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

CYP21A2-related disorder Pathogenic:1

Jul 11, 2024

PreventionGenetics, part of Exact Sciences

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: 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. -

Inborn genetic diseases Pathogenic:1

Apr 20, 2022

Ambry Genetics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: 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. -

Adenoma, cortisol-producing Pathogenic:1

Jul 01, 1998

OMIM

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

- -

Carcinoma, adrenocortical, androgen-secreting Pathogenic:1

Jul 01, 1998

OMIM

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

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Congenital adrenal hyperplasia Pathogenic:1

Dec 14, 2021

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: 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. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.39
BayesDel_addAF	Uncertain	0.064	T
BayesDel_noAF	Benign	-0.15
CADD	Uncertain	23
DANN	Uncertain	0.99
Eigen	Benign	0.054
Eigen_PC	Benign	0.10
FATHMM_MKL	Uncertain	0.88	D
MetaRNN	Benign	0.0097	T;T;T;T
MetaSVM	Benign	-0.97	T
PhyloP100		2.6
PrimateAI	Uncertain	0.50	T
PROVEAN	Benign	-0.90	N;.;N;.
REVEL	Uncertain	0.31
Sift	Benign	0.61	T;.;T;.
Sift4G	Benign	0.41	T;.;T;.
Polyphen		0.93	P;P;.;P
Vest4		0.88
MutPred		0.86		Gain of disorder (P = 0.1696);Gain of disorder (P = 0.1696);.;Gain of disorder (P = 0.1696);
MPC		1.2
ClinPred		0.98	D
GERP RS		4.0
gMVP		0.60
Mutation Taster		=11/89	disease causing (ClinVar)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.0		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs6471; hg19: chr6-32007887; COSMIC: COSV64479410; COSMIC: COSV64479410;