VCV000012151.55 - ClinVar

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

Germline

Classification

The aggregate germline classification for this variant, typically for a monogenic or Mendelian disorder as in the ACMG/AMP guidelines, or for response to a drug. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the aggregate classification.

(35)

Stars represent the aggregate review status, or the level of review supporting the aggregate germline classification for this VCV record. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the review status. The number of submissions which contribute to this review status is shown in parentheses.

Pathogenic/Likely pathogenic

criteria provided, multiple submitters, no conflicts

Somatic

No data submitted for somatic clinical impact

Somatic

No data submitted for oncogenicity

Variant Details

This variant is part of a Haplotype

NM_000500.7(CYP21A2):c.[844G>T;920_921insT;955C>T;1069C>T]

Identifiers

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

Variation ID: 12151 Accession: VCV000012151.55

Type and length

single nucleotide variant, 1 bp

Location

Cytogenetic: 6p21.33 6: 32040110 (GRCh38) [ NCBI UCSC ] 6: 32007887 (GRCh37) [ NCBI UCSC ]

Timeline in ClinVar

	First in ClinVar Help The date this variant first appeared in ClinVar with each type of classification.	Last submission Help The date of the most recent submission for each type of classification for this variant.	Last evaluated Help The most recent date that a submitter evaluated this variant for each type of classification.
Germline	Apr 4, 2013	Nov 30, 2024	Aug 15, 2024

HGVS

Nucleotide	Protein	Molecular consequence
NM_000500.9:c.844G>T MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.	NP_000491.4:p.Val282Leu	missense
NM_001128590.4:c.754G>T	NP_001122062.3:p.Val252Leu	missense
NM_001368143.2:c.439G>T	NP_001355072.1:p.Val147Leu	missense
NM_001368144.2:c.439G>T	NP_001355073.1:p.Val147Leu	missense
NC_000006.12:g.32040110G>T
NC_000006.11:g.32007887G>T
NG_007941.3:g.6806G>T
NG_008337.2:g.74265C>A
NG_045215.1:g.2339G>T
LRG_829:g.6806G>T
LRG_829t1:c.844G>T	LRG_829p1:p.Val282Leu

... more HGVS ... less HGVS

Protein change

V282L, V147L, V252L

Other names

V281L
CYP21A2*15

Canonical SPDI

NC_000006.12:32040109:G:T

Functional consequence Help The effect of the variant on RNA or protein function, based on experimental evidence from submitters.

Global minor allele frequency (GMAF) Help The global minor allele frequency calculated by the 1000 Genomes Project. The minor allele at this location is indicated in parentheses and may be different from the allele represented by this VCV record.

Allele frequency Help The frequency of the allele represented by this VCV record.

1000 Genomes Project 30x 0.01218

Links

ClinGen: CA121919 OMIM: 613815.0002 OMIM: 613815.0033 dbSNP: rs6471 VarSome

Genes

Gene	OMIM	ClinGen Gene Dosage Sensitivity Curation		Variation Viewer Help Links to Variation Viewer, a genome browser to view variation data from NCBI databases.	Related variants
Gene	OMIM	HI score Help The haploinsufficiency score for the gene, curated by ClinGen’s Dosage Sensitivity Curation task team.	TS score Help The triplosensitivity score for the gene, curated by ClinGen’s Dosage Sensitivity Curation task team.		Within gene Help The number of variants in ClinVar that are contained within this gene, with a link to view the list of variants.	All Help The number of variants in ClinVar for this gene, including smaller variants within the gene and larger CNVs that overlap or fully contain the gene.
CYP21A2		-	-	GRCh38 GRCh38 GRCh38 GRCh38 GRCh38 GRCh38 GRCh37	27	366
LOC106780800	-	-	-	GRCh38 GRCh38	-	308

Conditions - Germline

Condition Help The condition for this variant-condition (RCV) record in ClinVar.	Classification Help The aggregate germline classification for this variant-condition (RCV) record in ClinVar. The number of submissions that contribute to this aggregate classification is shown in parentheses. (# of submissions)	Review status Help The aggregate review status for this variant-condition (RCV) record in ClinVar. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the review status.	Last evaluated Help The most recent date that a submitter evaluated this variant for the condition.	Variation/condition record Help The RCV accession number, with most recent version number, for the variant-condition record, with a link to the RCV web page.
Adenoma, cortisol-producing	Pathogenic (1)	no assertion criteria provided	Jul 1, 1998	RCV000012935.2
Carcinoma, adrenocortical, androgen-secreting	Pathogenic (1)	no assertion criteria provided	Jul 1, 1998	RCV000012936.2
Classic congenital adrenal hyperplasia due to 21-hydroxylase deficiency	Pathogenic/Likely pathogenic (18)	criteria provided, multiple submitters, no conflicts	Aug 15, 2024	RCV000012934.34
Inborn genetic diseases	Pathogenic (1)	criteria provided, single submitter	Apr 20, 2022	RCV000210728.4
not provided	Pathogenic (12)	criteria provided, multiple submitters, no conflicts	Jan 30, 2024	RCV000711385.30
Congenital adrenal hyperplasia	Pathogenic (1)	criteria provided, single submitter	Dec 14, 2021	RCV001804725.1
CYP21A2-related disorder	Pathogenic (1)	no assertion criteria provided	Jul 11, 2024	RCV003407320.5

Submissions - Germline

Classification Help The submitted germline classification for each SCV record. (Last evaluated)	Review status Help Stars represent the review status, or the level of review supporting the submitted (SCV) record. This value is calculated by NCBI based on data from the submitter. Read our rules for calculating the review status. This column also includes a link to the submitter’s assertion criteria if provided, and the collection method. (Assertion criteria)	Condition Help The condition for the classification, provided by the submitter for this submitted (SCV) record. This column also includes the affected status and allele origin of individuals observed with this variant.	Submitter Help The submitting organization for this submitted (SCV) record. This column also includes the SCV accession and version number, the date this SCV first appeared in ClinVar, and the date that this SCV was last updated in ClinVar.	More information Help This column includes more information supporting the classification, including citations, the comment on classification, and detailed evidence provided as observations of the variant by the submitter.
Pathogenic (Jun 27, 2016)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Classic congenital adrenal hyperplasia due to 21-hydroxylase deficiency Affected status: no Allele origin: germline	Knight Diagnostic Laboratories, Oregon Health and Sciences University Study: CSER-NextGen Accession: SCV000494239.1 First in ClinVar: Sep 14, 2015 Last updated: Sep 14, 2015	Comment: 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 … (more) 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 â€“ hydroxylase deficiency. We have confirmed this finding in our laboratory using Sanger sequencing. (less)
Pathogenic (May 18, 2017)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Classic congenital adrenal hyperplasia due to 21-hydroxylase deficiency Affected status: unknown Allele origin: unknown	Fulgent Genetics, Fulgent Genetics Accession: SCV000611260.1 First in ClinVar: Sep 14, 2015 Last updated: Sep 14, 2015
Pathogenic (Oct 17, 2014)	criteria provided, single submitter (LMM Criteria) Method: clinical testing	Classic congenital adrenal hyperplasia due to 21-hydroxylase deficiency (Autosomal recessive inheritance) Affected status: not provided Allele origin: germline	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine Accession: SCV000245595.1 First in ClinVar: Sep 14, 2015 Last updated: Sep 14, 2015	Publications: PubMed (4) PubMed: 23359698‚ 23359706‚ 21609351‚ 20661889 Comment: 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 … (more) 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). (less) Number of individuals with the variant: 2
Pathogenic (Dec 26, 2019)	criteria provided, single submitter (Myriad Women's Health Autosomal Recessive and X-Linked Classification Criteria (2019)) Method: clinical testing	Classic congenital adrenal hyperplasia due to 21-hydroxylase deficiency Affected status: unknown Allele origin: unknown	Myriad Genetics, Inc. Accession: SCV001193785.2 First in ClinVar: Apr 06, 2020 Last updated: Jul 06, 2020	Publications: PubMed (7) PubMed: 20661889‚ 14513879‚ 23359698‚ 20926536‚ 1644925‚ 1864962‚ 2249999 Comment: 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 … (more) 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. (less)
Pathogenic (Feb 18, 2021)	criteria provided, single submitter (GeneDx Variant Classification Process June 2021) Method: clinical testing	Not Provided Affected status: yes Allele origin: germline	GeneDx Accession: SCV001805044.1 First in ClinVar: Aug 21, 2021 Last updated: Aug 21, 2021	Comment: 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, … (more) 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) (less)
Pathogenic (Feb 28, 2023)	criteria provided, single submitter (Athena Diagnostics Criteria) Method: clinical testing	not provided Affected status: unknown Allele origin: unknown	Athena Diagnostics Accession: SCV000841748.4 First in ClinVar: Oct 20, 2018 Last updated: Jan 26, 2024	Publications: PubMed (18) PubMed: 3260007‚ 33604243‚ 31586465‚ 31446012‚ 30968594‚ 29412390‚ 26804566‚ 25041270‚ 21609351‚ 20926536‚ 7749410‚ 7635470‚ 1644925‚ 1864962‚ 20661889‚ 23359698‚ 24953648‚ 2249999 Comment: 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 … (more) 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). (less)
Pathogenic (Jan 30, 2024)	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015)) Method: clinical testing	not provided Affected status: unknown Allele origin: germline	Labcorp Genetics (formerly Invitae), Labcorp Accession: SCV002242900.3 First in ClinVar: Mar 28, 2022 Last updated: Feb 20, 2024	Publications: PubMed (7) PubMed: 1644925‚ 23359698‚ 24953648‚ 26804566‚ 31344365‚ 1864962‚ 2249999 Comment: 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). … (more) 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. (less)
Pathogenic (Apr 20, 2022)	criteria provided, single submitter (Ambry Variant Classification Scheme 2023) Method: clinical testing	Inborn genetic diseases Affected status: unknown Allele origin: germline	Ambry Genetics Accession: SCV000263011.7 First in ClinVar: Apr 09, 2016 Last updated: May 01, 2024	Publications: PubMed (5) PubMed: 20661889‚ 23359698‚ 23359706‚ 25041270‚ 28161392 Comment: 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 … (more) 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. (less)
Pathogenic (Apr 28, 2023)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	not provided Affected status: yes Allele origin: germline	Clinical Genetics Laboratory, Skane University Hospital Lund Accession: SCV005196637.1 First in ClinVar: Aug 25, 2024 Last updated: Aug 25, 2024
Pathogenic (Aug 15, 2024)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Classic congenital adrenal hyperplasia due to 21-hydroxylase deficiency Affected status: yes Allele origin: germline	Molecular Genetics and NGS Laboratory, Hospital Fundacion Valle Del Lili Accession: SCV005200514.1 First in ClinVar: Sep 08, 2024 Last updated: Sep 08, 2024	Comment: Combined evidence strength is Very Strong (score = 9): ClinVar classifies this variant as Pathogenic, 2 stars. backed by functional studies (PS3). Combined evidence strength … (more) 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. (less) Number of individuals with the variant: 1 Age: 20-29 years Sex: female Ethnicity/Population group: Latino Geographic origin: Colombia
Pathogenic (Oct 26, 2017)	criteria provided, single submitter (Classification criteria August 2017) Method: clinical testing	Classic congenital adrenal hyperplasia due to 21-hydroxylase deficiency (Autosomal recessive inheritance) Affected status: yes Allele origin: maternal	Institute of Human Genetics Munich, Klinikum Rechts Der Isar, TU München Accession: SCV000680185.1 First in ClinVar: Feb 08, 2018 Last updated: Feb 08, 2018	Zygosity: Compound Heterozygote Sex: female Tissue: blood
Pathogenic (Apr 23, 2018)	criteria provided, single submitter (EGL ClinVar v180209 classification definitions) Method: clinical testing	not provided Affected status: unknown Allele origin: germline	Eurofins Ntd Llc (ga) Accession: SCV000854780.1 First in ClinVar: Dec 15, 2018 Last updated: Dec 15, 2018	Publications: PubMed (1) PubMed: 23359698 Other databases http://www.egl-eurofins.com/emvc… http://www.egl-eurofins.com/emvclass/emvclass.php?approved_symbol=CYP21A2 Number of individuals with the variant: 10 Zygosity: Homozygote, Single Heterozygote Sex: mixed
Pathogenic (May 28, 2019)	criteria provided, single submitter (Mendelics Assertion Criteria 2017) Method: clinical testing	Classic congenital adrenal hyperplasia due to 21-hydroxylase deficiency Affected status: unknown Allele origin: unknown	Mendelics Accession: SCV001137080.1 First in ClinVar: Jan 13, 2020 Last updated: Jan 13, 2020
Pathogenic (Apr 30, 2015)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	not provided Affected status: yes Allele origin: germline	Clinical Genetics and Genomics, Karolinska University Hospital Accession: SCV001449819.1 First in ClinVar: Dec 12, 2020 Last updated: Dec 12, 2020	Number of individuals with the variant: 55
Pathogenic (Dec 14, 2021)	criteria provided, single submitter (LabCorp Variant Classification Summary - May 2015) Method: clinical testing	Congenital adrenal hyperplasia Affected status: unknown Allele origin: germline	Women's Health and Genetics/Laboratory Corporation of America, LabCorp Accession: SCV002051107.1 First in ClinVar: Jan 08, 2022 Last updated: Jan 08, 2022	Publications: PubMed (3) PubMed: 7749410‚ 10857554‚ 32442933 Comment: 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 … (more) 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. (less)
Pathogenic (Jan 05, 2022)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Classic congenital adrenal hyperplasia due to 21-hydroxylase deficiency Affected status: yes Allele origin: germline	DASA Accession: SCV002061154.1 First in ClinVar: Jan 22, 2022 Last updated: Jan 22, 2022	Publications: PubMed (15) PubMed: 20301350‚ 2788081‚ 3260007‚ 1496017‚ 7635470‚ 1985465‚ 9661649‚ 8081391‚ 25356970‚ 23359698‚ 30968594‚ 29996815‚ 26804566‚ 26206692‚ 27041116 Comment: 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; … (more) 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. (less) Number of individuals with the variant: 3 Sex: female Geographic origin: Brazil;Uruguay
Pathogenic (Mar 24, 2022)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Not provided Affected status: yes Allele origin: germline	AiLife Diagnostics, AiLife Diagnostics Accession: SCV002502920.1 First in ClinVar: Apr 23, 2022 Last updated: Apr 23, 2022	Publications: PubMed (32) PubMed: 3260007‚ 24953648‚ 29525066‚ 30609409‚ 29412390‚ 20661889‚ 10908170‚ 14513879‚ 31605362‚ 28644547‚ 21646730‚ 23359706‚ 12038604‚ 31980526‚ 31446012‚ 34355878‚ 10408786‚ 31344365‚ 25538881‚ 23359698‚ 30656636‚ 30487145‚ 25481255‚ 32714392‚ 27785393‚ 31586465‚ 2249999‚ 33604243‚ 26804566‚ 1864962‚ 30968594‚ 31159521 Number of individuals with the variant: 2 Secondary finding: no
Pathogenic (May 22, 2022)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Classic congenital adrenal hyperplasia due to 21-hydroxylase deficiency Affected status: yes Allele origin: germline	3billion Accession: SCV002521256.1 First in ClinVar: Jun 03, 2022 Last updated: Jun 03, 2022	Publications: PubMed (3) PubMed: 21609351‚ 10720040‚ 20661889 Comment: 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 … (more) 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. (less) Clinical Features: Elevated circulating 17-hydroxyprogesterone concentration (present) , Vomiting (present) , Dehydration (present) , Hyponatremia (present) , Hyperkalemia (present) , Short stature (present) Zygosity: Single Heterozygote
Likely pathogenic (-)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Classic congenital adrenal hyperplasia due to 21-hydroxylase deficiency (Autosomal recessive inheritance) Affected status: yes Allele origin: germline	Lifecell International Pvt. Ltd Accession: SCV003852661.1 First in ClinVar: Apr 09, 2023 Last updated: Apr 09, 2023	Publications: PubMed (1) PubMed: 31344365 Comment: 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 … (more) 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. (less) Zygosity: Compound Heterozygote Ethnicity/Population group: Asian Geographic origin: India
Pathogenic (Feb 28, 2023)	criteria provided, single submitter (Quest Diagnostics criteria) Method: clinical testing	not provided Affected status: unknown Allele origin: unknown	Quest Diagnostics Nichols Institute San Juan Capistrano Accession: SCV001469965.4 First in ClinVar: Jan 26, 2021 Last updated: Jan 06, 2024	Publications: PubMed (18) PubMed: 3260007‚ 33604243‚ 31586465‚ 31446012‚ 30968594‚ 29412390‚ 26804566‚ 25041270‚ 21609351‚ 20926536‚ 7749410‚ 7635470‚ 1644925‚ 1864962‚ 20661889‚ 23359698‚ 24953648‚ 2249999 Comment: 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 … (more) 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. (less)
Pathogenic (Dec 08, 2023)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	not provided Affected status: unknown Allele origin: germline	Revvity Omics, Revvity Accession: SCV002018115.3 First in ClinVar: Nov 29, 2021 Last updated: Feb 04, 2024
Likely pathogenic (Mar 26, 2024)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Classic congenital adrenal hyperplasia due to 21-hydroxylase deficiency Affected status: unknown Allele origin: germline	Center for Genomic Medicine, King Faisal Specialist Hospital and Research Center Accession: SCV004806938.1 First in ClinVar: Apr 06, 2024 Last updated: Apr 06, 2024
Pathogenic (Feb 01, 2024)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: curation	Classic congenital adrenal hyperplasia due to 21-hydroxylase deficiency Affected status: no Allele origin: germline	Laboratory of Medical Genetics, National & Kapodistrian University of Athens Accession: SCV005051737.1 First in ClinVar: Jun 17, 2024 Last updated: Jun 17, 2024
Pathogenic (Jul 16, 2023)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Classic congenital adrenal hyperplasia due to 21-hydroxylase deficiency (Autosomal recessive inheritance) Affected status: unknown Allele origin: germline	Victorian Clinical Genetics Services, Murdoch Childrens Research Institute Additional submitter: Shariant Australia, Australian Genomics Accession: SCV002769514.2 First in ClinVar: Dec 24, 2022 Last updated: Jul 23, 2024	Publications: PubMed (1) PubMed: 23359698 Comment: 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 … (more) 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 (less)
Pathogenic (-)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Classic congenital adrenal hyperplasia due to 21-hydroxylase deficiency Affected status: yes Allele origin: germline	Juno Genomics, Hangzhou Juno Genomics, Inc Accession: SCV005416532.1 First in ClinVar: Nov 30, 2024 Last updated: Nov 30, 2024	Comment: PM3_VeryStrong+PS3
Pathogenic (Jul 01, 1998)	no assertion criteria provided Method: literature only	ADRENAL HYPERPLASIA, CONGENITAL, DUE TO 21-HYDROXYLASE DEFICIENCY, NONCLASSIC TYPE Affected status: not provided Allele origin: germline	OMIM Accession: SCV000033175.1 First in ClinVar: Apr 04, 2013 Last updated: Apr 04, 2013	Publications: PubMed (7) PubMed: 3260007‚ 2788081‚ 1985465‚ 1496017‚ 7635470‚ 8081391‚ 9661649 Comment on evidence: In 9 patients with nonclassic 21-hydroxylase deficiency (201910) associated with HLA-B14;DR1, Speiser et al. (1988) found a change in codon 281 from GTG, encoding valine, … (more) In 9 patients with nonclassic 21-hydroxylase deficiency (201910) associated with HLA-B14;DR1, Speiser et al. (1988) found a change in codon 281 from GTG, encoding valine, to TTG, encoding leucine. Speiser et al. (1989) concluded that this codon 281 mutation is a consistent change in nonclassic 21-hydroxylase deficiency associated with HLA-B14;DR1. The val281-to-leu mutation (V281L), found in association with the HLA-B14;DR1 haplotype, accounts for 75 to 80% of nonclassic 21-hydroxylase deficiency (Mornet et al., 1991). This mutation was observed in several patients by Wedell et al. (1992), who referred to it as VAL282LEU. In an analysis of steroid 21-hydroxylase gene mutations in the Spanish population, Ezquieta et al. (1995) found that the most frequent mutation causing the late onset form of disease (present in 15 of 38 patients) was val281 to leu, found in 18 of 30 chromosomes (37%). This mutation is found in 34% of all cases of the nonclassic type (White et al., 1994). In samples from 2 patients (1 with a cortisol-producing adenoma and 1 with an androgen-secreting adrenocortical carcinoma), Beuschlein et al. (1998) detected the heterozygous germline mutation val281 to leu in exon 7. (less)
Pathogenic (Jul 01, 1998)	no assertion criteria provided Method: literature only	ADENOMA, CORTISOL-PRODUCING Affected status: not provided Allele origin: germline	OMIM Accession: SCV000033176.1 First in ClinVar: Apr 04, 2013 Last updated: Apr 04, 2013	Publications: PubMed (7) PubMed: 3260007‚ 2788081‚ 1985465‚ 1496017‚ 7635470‚ 8081391‚ 9661649 Comment on evidence: In 9 patients with nonclassic 21-hydroxylase deficiency (201910) associated with HLA-B14;DR1, Speiser et al. (1988) found a change in codon 281 from GTG, encoding valine, … (more) In 9 patients with nonclassic 21-hydroxylase deficiency (201910) associated with HLA-B14;DR1, Speiser et al. (1988) found a change in codon 281 from GTG, encoding valine, to TTG, encoding leucine. Speiser et al. (1989) concluded that this codon 281 mutation is a consistent change in nonclassic 21-hydroxylase deficiency associated with HLA-B14;DR1. The val281-to-leu mutation (V281L), found in association with the HLA-B14;DR1 haplotype, accounts for 75 to 80% of nonclassic 21-hydroxylase deficiency (Mornet et al., 1991). This mutation was observed in several patients by Wedell et al. (1992), who referred to it as VAL282LEU. In an analysis of steroid 21-hydroxylase gene mutations in the Spanish population, Ezquieta et al. (1995) found that the most frequent mutation causing the late onset form of disease (present in 15 of 38 patients) was val281 to leu, found in 18 of 30 chromosomes (37%). This mutation is found in 34% of all cases of the nonclassic type (White et al., 1994). In samples from 2 patients (1 with a cortisol-producing adenoma and 1 with an androgen-secreting adrenocortical carcinoma), Beuschlein et al. (1998) detected the heterozygous germline mutation val281 to leu in exon 7. (less)
Pathogenic (Jul 01, 1998)	no assertion criteria provided Method: literature only	CARCINOMA, ADRENOCORTICAL, ANDROGEN-SECRETING Affected status: not provided Allele origin: germline	OMIM Accession: SCV000033177.1 First in ClinVar: Apr 04, 2013 Last updated: Apr 04, 2013	Publications: PubMed (7) PubMed: 3260007‚ 2788081‚ 1985465‚ 1496017‚ 7635470‚ 8081391‚ 9661649 Comment on evidence: In 9 patients with nonclassic 21-hydroxylase deficiency (201910) associated with HLA-B14;DR1, Speiser et al. (1988) found a change in codon 281 from GTG, encoding valine, … (more) In 9 patients with nonclassic 21-hydroxylase deficiency (201910) associated with HLA-B14;DR1, Speiser et al. (1988) found a change in codon 281 from GTG, encoding valine, to TTG, encoding leucine. Speiser et al. (1989) concluded that this codon 281 mutation is a consistent change in nonclassic 21-hydroxylase deficiency associated with HLA-B14;DR1. The val281-to-leu mutation (V281L), found in association with the HLA-B14;DR1 haplotype, accounts for 75 to 80% of nonclassic 21-hydroxylase deficiency (Mornet et al., 1991). This mutation was observed in several patients by Wedell et al. (1992), who referred to it as VAL282LEU. In an analysis of steroid 21-hydroxylase gene mutations in the Spanish population, Ezquieta et al. (1995) found that the most frequent mutation causing the late onset form of disease (present in 15 of 38 patients) was val281 to leu, found in 18 of 30 chromosomes (37%). This mutation is found in 34% of all cases of the nonclassic type (White et al., 1994). In samples from 2 patients (1 with a cortisol-producing adenoma and 1 with an androgen-secreting adrenocortical carcinoma), Beuschlein et al. (1998) detected the heterozygous germline mutation val281 to leu in exon 7. (less)
Pathogenic (-)	no assertion criteria provided Method: clinical testing	not provided Affected status: yes Allele origin: germline	Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC) Study: VKGL Data-share Consensus Accession: SCV001800488.1 First in ClinVar: Aug 21, 2021 Last updated: Aug 21, 2021
Pathogenic (Oct 09, 2023)	no assertion criteria provided Method: clinical testing	Classic congenital adrenal hyperplasia due to 21-hydroxylase deficiency Affected status: yes Allele origin: germline	Zotz-Klimas Genetics Lab, MVZ Zotz Klimas Accession: SCV004041737.1 First in ClinVar: Oct 14, 2023 Last updated: Oct 14, 2023
Pathogenic (Jan 06, 2020)	no assertion criteria provided Method: curation	Classic congenital adrenal hyperplasia due to 21-hydroxylase deficiency Affected status: unknown Allele origin: germline	Reproductive Health Research and Development, BGI Genomics Accession: SCV001142354.1 First in ClinVar: Jan 13, 2020 Last updated: Jan 13, 2020	Comment: 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 … (more) 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. (less)
Pathogenic (-)	no assertion criteria provided Method: clinical testing	not provided Affected status: yes Allele origin: germline	Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+ Additional submitter: Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen Study: VKGL Data-share Consensus Accession: SCV001957946.1 First in ClinVar: Oct 02, 2021 Last updated: Oct 02, 2021
Pathogenic (Nov 18, 2022)	no assertion criteria provided Method: clinical testing	not provided Affected status: yes Allele origin: unknown	Department of Pathology and Laboratory Medicine, Sinai Health System Additional submitter: Franklin by Genoox Study: The Canadian Open Genetics Repository (COGR) Accession: SCV001552008.2 First in ClinVar: Apr 13, 2021 Last updated: Nov 29, 2022	Comment: 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 … (more) 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. (less)
Pathogenic (Jul 11, 2024)	no assertion criteria provided Method: clinical testing	CYP21A2-related condition Affected status: unknown Allele origin: germline	PreventionGenetics, part of Exact Sciences Accession: SCV004114182.2 First in ClinVar: Nov 20, 2023 Last updated: Oct 08, 2024	Comment: 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 … (more) 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. (less)
not provided (-)	no classification provided Method: literature only	Classic congenital adrenal hyperplasia due to 21-hydroxylase deficiency Affected status: not provided Allele origin: unknown	GeneReviews Accession: SCV000086803.2 First in ClinVar: Oct 01, 2013 Last updated: Oct 01, 2022	Publications: PubMed (1) PubMed: 20301350 BookShelf: NBK1171 BookShelf: NBK1171
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Comment:

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 â€“ hydroxylase deficiency. We have confirmed this finding in our laboratory using Sanger sequencing.

Comment:

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).

Comment:

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.

Comment:

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)

Comment:

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).

Comment:

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.

Comment:

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.

Comment:

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.

Comment:

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.

Comment:

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.

Comment:

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.

Comment:

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.

Comment:

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.

Comment:

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

Comment:

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.

Comment:

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.

Comment:

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.

Germline Functional Evidence

There is no functional evidence in ClinVar for this variation. If you have generated functional data for this variation, please consider submitting that data to ClinVar.

Comment:

Citations for germline classification of this variant

Title	Author	Journal	Year	Link
Rare Coexistence of Congenital Adrenal Hyperplasia due to 21-Hydroxylase Deficiency and Turner Syndrome: A Case Report and Brief Literature Review.	Inácio I	Journal of clinical research in pediatric endocrinology	2023	PMID: 34355878
CYP21A2 mutations in pediatric patients with congenital adrenal hyperplasia in Costa Rica.	Umaña-Calderón A	Molecular genetics and metabolism reports	2021	PMID: 33604243
p.Gln318X and p.Val281Leu as the Major Variants of CYP21A2 Gene in Children with Idiopathic Premature Pubarche.	Soveizi M	International journal of endocrinology	2020	PMID: 32714392
Molecular analysis of the CYP21A2 gene in dried blood spot samples.	Marino S	Medicina	2020	PMID: 32442933
Precision medicine integrating whole-genome sequencing, comprehensive metabolomics, and advanced imaging.	Hou YC	Proceedings of the National Academy of Sciences of the United States of America	2020	PMID: 31980526
The prevalence of heterozygous CYP21A2 deficiency in patients with idiopathic acne, hirsutism, or both.	Gao Y	Endocrine	2020	PMID: 31605362
21-Hydroxylase deficiency: Mutational spectrum and Genotype-Phenotype relations analyses by next-generation sequencing and multiplex ligation-dependent probe amplification.	Turan I	European journal of medical genetics	2020	PMID: 31586465
Analysis of phenotypes and genotypes in 84 patients with 21-Hydroxylase deficiency in southern China.	Hou L	Steroids	2019	PMID: 31446012
Novel non-classic CYP21A2 variants, including combined alleles, identified in patients with congenital adrenal hyperplasia.	Karlsson L	Clinical biochemistry	2019	PMID: 31344365
[Clinical features and genetic characteristics of 33 patients with simple virilizing form of 21-hydroxylase deficiency].	Zeng LT	Zhonghua nei ke za zhi	2019	PMID: 31159521
Genotype-phenotype correlation study and mutational and hormonal analysis in a Chinese cohort with 21-hydroxylase deficiency.	Xu C	Molecular genetics & genomic medicine	2019	PMID: 30968594
Study of Human Leukocyte Antigen (HLA) in 13 cases of familial frontal fibrosing alopecia: CYP21A2 gene p.V281L mutation from congenital adrenal hyperplasia linked to HLA class I haplotype HLA-A33:01; B14:02; C*08:02 as a genetic marker.	Porriño-Bustamante ML	The Australasian journal of dermatology	2019	PMID: 30656636
Interpretation of Genomic Sequencing Results in Healthy and Ill Newborns: Results from the BabySeq Project.	Ceyhan-Birsoy O	American journal of human genetics	2019	PMID: 30609409
High-frequency actionable pathogenic exome variants in an average-risk cohort.	Rego S	Cold Spring Harbor molecular case studies	2018	PMID: 30487145
Phenotype heterogeneity of congenital adrenal hyperplasia due to genetic mosaicism and concomitant nephrogenic diabetes insipidus in a sibling.	Kor Y	BMC medical genetics	2018	PMID: 29996815
[Diffuse hypertrichosis revealing non-classical congenital adrenal hyperplasia].	Berthin C	Annales de dermatologie et de venereologie	2018	PMID: 29525066
A genetic epidemiology study of congenital adrenal hyperplasia in Italy.	Gialluisi A	Clinical genetics	2018	PMID: 28644547
Growth hormone deficiency with advanced bone age: phenotypic interaction between GHRH receptor and CYP21A2 mutations diagnosed by sanger and whole exome sequencing.	Correa FA	Archives of endocrinology and metabolism	2017	PMID: 29412390
[Recommendations for the diagnosis and treatment of classic forms of 21-hydroxylase-deficient congenital adrenal hyperplasia].	Rodríguez A	Anales de pediatria (Barcelona, Spain : 2003)	2017	PMID: 28161392
Molecular genetic analysis in 93 patients and 193 family members with classical congenital adrenal hyperplasia due to 21-hydroxylase deficiency in Croatia.	Dumic KK	The Journal of steroid biochemistry and molecular biology	2017	PMID: 27041116
Detection of mutations in the CYP21A2 gene: genotype-phenotype correlation in Slovenian couples with conceiving problems.	Stangler Herodež Š	Balkan journal of medical genetics : BJMG	2016	PMID: 27785393
21-hydroxylase deficiency-induced congenital adrenal hyperplasia in 230 Chinese patients: Genotype-phenotype correlation and identification of nine novel mutations.	Wang R	Steroids	2016	PMID: 26804566
21-Hydroxylase-Deficient Congenital Adrenal Hyperplasia.	Adam MP	-	2016	PMID: 20301350
CYP21A2 mutation analysis in Korean patients with congenital adrenal hyperplasia using complementary methods: sequencing after long-range PCR and restriction fragment length polymorphism analysis with multiple ligation-dependent probe amplification assay.	Hong G	Annals of laboratory medicine	2015	PMID: 26206692
Genetic defects of the CYP21A2 gene in girls with premature adrenarche.	Skordis N	Journal of endocrinological investigation	2015	PMID: 25481255
Enhanced utility of family-centered diagnostic exome sequencing with inheritance model-based analysis: results from 500 unselected families with undiagnosed genetic conditions.	Farwell KD	Genetics in medicine : official journal of the American College of Medical Genetics	2015	PMID: 25356970
The spectrum of clinical, hormonal and molecular findings in 280 individuals with nonclassical congenital adrenal hyperplasia caused by mutations of the CYP21A2 gene.	Livadas S	Clinical endocrinology	2015	PMID: 25041270
In vitro functional studies of rare CYP21A2 mutations and establishment of an activity gradient for nonclassic mutations improve phenotype predictions in congenital adrenal hyperplasia.	Barbaro M	Clinical endocrinology	2015	PMID: 24953648
Phenotypic variability of hyperandrogenemia in females heterozygous for CYP21A2 mutations.	Neocleous V	Indian journal of endocrinology and metabolism	2014	PMID: 25538881
Structure-phenotype correlations of human CYP21A2 mutations in congenital adrenal hyperplasia.	Haider S	Proceedings of the National Academy of Sciences of the United States of America	2013	PMID: 23359706
Genotype-phenotype correlation in 1,507 families with congenital adrenal hyperplasia owing to 21-hydroxylase deficiency.	New MI	Proceedings of the National Academy of Sciences of the United States of America	2013	PMID: 23359698
Cushing's disease in a patient with steroid 21-hydroxylase deficiency.	Haase M	Endocrine journal	2011	PMID: 21646730
Steroid 21-hydroxylase gene mutational spectrum in 454 Argentinean patients: genotype-phenotype correlation in a large cohort of patients with congenital adrenal hyperplasia.	Marino R	Clinical endocrinology	2011	PMID: 21609351
Comprehensive genetic analysis of 182 unrelated families with congenital adrenal hyperplasia due to 21-hydroxylase deficiency.	Finkielstain GP	The Journal of clinical endocrinology and metabolism	2011	PMID: 20926536
Carrier detection and prenatal diagnosis of congenital adrenal hyperplasia must identify 'apparently mild' CYP21A2 alleles which associate neonatal salt-wasting disease.	Ezquieta B	Prenatal diagnosis	2010	PMID: 20661889
Steroid 21-hydroxylase (P450c21) naturally occurring mutants I172N, V281L and I236n/V237E/M239K exert a dominant negative effect on enzymatic activity when co-expressed with the wild-type protein.	Félix-López X	Journal of pediatric endocrinology & metabolism : JPEM	2003	PMID: 14513879
Application of polymerase chain reaction with oligoligation assay to determine genotype in individuals presenting with congenital adrenal hyperplasia.	Hogg JE	Annals of clinical biochemistry	2002	PMID: 12038604
Mutations in the CYP21 B gene in a Chilean population with simple virilizing congenital adrenal hyperplasia.	Fardella CE	Journal of endocrinological investigation	2000	PMID: 10908170
Congenital adrenal hyperplasia due to 21-hydroxylase deficiency.	White PC	Endocrine reviews	2000	PMID: 10857554
Predicting phenotype in steroid 21-hydroxylase deficiency? Comprehensive genotyping in 155 unrelated, well defined patients from southern Germany.	Krone N	The Journal of clinical endocrinology and metabolism	2000	PMID: 10720040
A rapid screening for steroid 21-hydroxylase mutations in patients with congenital adrenal hyperplasia. Mutations in brief no. 247. Online.	Kapelari K	Human mutation	1999	PMID: 10408786
Steroid 21-hydroxylase mutations and 21-hydroxylase messenger ribonucleic acid expression in human adrenocortical tumors.	Beuschlein F	The Journal of clinical endocrinology and metabolism	1998	PMID: 9661649
Screening of CYP21 gene mutations in 129 French patients affected by steroid 21-hydroxylase deficiency.	Barbat B	Human mutation	1995	PMID: 7749410
Analysis of steroid 21-hydroxylase gene mutations in the Spanish population.	Ezquieta B	Human genetics	1995	PMID: 7635470
Mutations in steroid 21-hydroxylase (CYP21).	White PC	Human mutation	1994	PMID: 8081391
Disease expression and molecular genotype in congenital adrenal hyperplasia due to 21-hydroxylase deficiency.	Speiser PW	The Journal of clinical investigation	1992	PMID: 1644925
Steroid 21-hydroxylase deficiency: three additional mutated alleles and establishment of phenotype-genotype relationships of common mutations.	Wedell A	Proceedings of the National Academy of Sciences of the United States of America	1992	PMID: 1496017
Distribution of deletions and seven point mutations on CYP21B genes in three clinical forms of steroid 21-hydroxylase deficiency.	Mornet E	American journal of human genetics	1991	PMID: 1985465
Mutations of P450c21 (steroid 21-hydroxylase) at Cys428, Val281, and Ser268 result in complete, partial, or no loss of enzymatic activity, respectively.	Wu DA	The Journal of clinical investigation	1991	PMID: 1864962
Determination of functional effects of mutations in the steroid 21-hydroxylase gene (CYP21) using recombinant vaccinia virus.	Tusie-Luna MT	The Journal of biological chemistry	1990	PMID: 2249999
Clinical and genetic characterization of nonclassic 21-hydroxylase deficiency.	Speiser PW	Endocrine research	1989	PMID: 2788081
Molecular genetic analysis of nonclassic steroid 21-hydroxylase deficiency associated with HLA-B14,DR1.	Speiser PW	The New England journal of medicine	1988	PMID: 3260007
http://www.egl-eurofins.com/emvclass/emvclass.php?approved_symbol=CYP21A2	-	-	-	-
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Text-mined citations for rs6471 ...

These citations are identified by LitVar using the rs number, so they may include citations for more than one variant at this location. Please review the LitVar results carefully for your variant of interest.

Record last updated Nov 30, 2024

ClinVar Genomic variation as it relates to human health

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

Variant Details

Genes

Conditions - Germline

Submissions - Germline

Germline Functional Evidence

Citations for germline classification of this variant

Text-mined citations for rs6471 ...