6-32040535-C-T

Position:

chr6-32040535-C-T

Variant summary

Our verdict is Pathogenic. Variant got 12 ACMG points: 12P and 0B. PP3_StrongPP5_Very_Strong

The NM_000500.9(CYP21A2):c.1069C>T(p.Arg357Trp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000301 in 1,460,002 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Pathogenic (★★).

Frequency

Genomes: 𝑓 0.000086 ( 0 hom., cov: 33)

Exomes 𝑓: 0.000030 ( 0 hom. )

Failed GnomAD Quality Control

Consequence

CYP21A2
NM_000500.9 missense

Scores

Clinical Significance

Pathogenic criteria provided, multiple submitters, no conflicts P:16O:1

Conservation

PhyloP100: 0.984

Variant links:

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 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Pathogenic. Variant got 12 ACMG points.

PP3

MetaRNN computational evidence supports a deleterious effect, 0.974

PP5

Variant 6-32040535-C-T is Pathogenic according to our data. Variant chr6-32040535-C-T is described in ClinVar as [Pathogenic]. Clinvar id is 12152.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr6-32040535-C-T is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
CYP21A2	NM_000500.9 link	c.1069C>T	p.Arg357Trp	missense_variant	8/10	ENST00000644719.2	NP_000491.4	P08686Q16874Q08AG9
CYP21A2	NM_001128590.4 link	c.979C>T	p.Arg327Trp	missense_variant	7/9		NP_001122062.3	P08686Q08AG9
CYP21A2	NM_001368143.2 link	c.664C>T	p.Arg222Trp	missense_variant	8/10		NP_001355072.1
CYP21A2	NM_001368144.2 link	c.664C>T	p.Arg222Trp	missense_variant	7/9		NP_001355073.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
CYP21A2	ENST00000644719.2 link	c.1069C>T	p.Arg357Trp	missense_variant	8/10		NM_000500.9	ENSP00000496625.1		Q16874

Frequencies

GnomAD3 genomes

AF:

0.0000858

AC:

AN:

151542

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.0000658

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00159

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000591

Gnomad OTH

AF:

0.00

GnomAD4 exome

AF:

0.0000301

AC:

AN:

1460002

Hom.:

Cov.:

AF XY:

0.0000330

AC XY:

AN XY:

726382

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.0000899

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.000153

Gnomad4 SAS exome

AF:

0.0000464

Gnomad4 FIN exome

AF:

0.0000377

Gnomad4 NFE exome

AF:

0.0000207

Gnomad4 OTH exome

AF:

0.0000829

GnomAD4 genome

Data not reliable, filtered out with message: AS_VQSR

AF:

0.0000857

AC:

AN:

151662

Hom.:

Cov.:

AF XY:

0.0000809

AC XY:

AN XY:

74156

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.0000657

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00160

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000591

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.000144

Hom.:

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:16Other:1

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Classic congenital adrenal hyperplasia due to 21-hydroxylase deficiency

Pathogenic:10Other:1

Pathogenic, criteria provided, single submitter	clinical testing	DASA	Jan 05, 2022	The c.1069C>T;p.(Arg357Trp) missense variant has been observed in affected individual(s) and ClinVar contains an entry for this variant (ClinVar ID: 12152; OMIM: 613815.0003; PMID: 20301350; 10720040; 26804566; 26206692; 25227725; 24904866; 24077358; 23359698; 23166432; 21329531; 10496074; 9215318; 9215318; 30968594; 29996815; 26804566; 20301350; 26206692) - PS4. Well-established in vitro or in vivo functional studies support a damaging effect on the gene or gene product (PMID: 2303461, 21134444, 1644925) - PS3_moderate. The p.(Arg357Trp) was detected in trans with a pathogenic variant (PMID: 30968594; 29996815; 26804566; 26206692) - PM3_strong. Pathogenic missense variant in this residue have been reported (Clinvar ID: 988494) - PM5. The variant co-segregated with disease in multiple affected family members (PMID: 29996815; 27041116) - PP1. Multiple lines of computational evidence support a deleterious effect on the gene or gene product - PP3. In summary, the currently available evidence indicates that the variant is pathogenic. -
Pathogenic, no assertion criteria provided	literature only	OMIM	Jul 01, 1997	- -
Pathogenic, criteria provided, single submitter	clinical testing	3billion	May 22, 2022	The variant is observed at an extremely low frequency in the gnomAD v2.1.1 dataset (total allele frequency: 0.002%). The variant is located in a mutational hot spot and/or well-established functional domain in which established pathogenic variants have been reported. In silico tool predictions suggest damaging effect of the variant on gene or gene product (REVEL: 0.68; 3Cnet: 0.98). Same nucleotide change resulting in same amino acid change has been previously reported as pathogenic/likely pathogenic with strong evidence (ClinVar ID: VCV000012152). Different missense changes at the same codon (p.Arg357Gln, p.Arg357Pro) have been reported to be associated with CYP21A2 related disorder (ClinVar ID: VCV000988494 / PMID: 9099839, 9187661). Therefore, this variant is classified as pathogenic according to the recommendation of ACMG/AMP guideline. -
Pathogenic, criteria provided, single submitter	clinical testing	Neuberg Centre For Genomic Medicine, NCGM	Jun 22, 2023	The observed missense c.1069C>Tp.Arg357Trp variant in CYP21A2 gene has been reported previously in homozygous or compound heterozygous state in individuals affected with Congenital adrenal hyperplasia CAH Tippabathani et al., 2023. Experimental studies have shown that this missense change affects CYP21A2 function Chiou et al., 1190; Gaffney et al., 2010. This variant is reported with the allele frequency of 0.001% in the gnomAD Exomes. 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. About 203 total individuals have variant depth in the 0 - 5 range in gnomAD database. This variant has been reported to the ClinVar database as Pathogenic multiple submitters. The amino acid Arg at position 357 is changed to a Trp changing protein sequence and it might alter its composition and physico-chemical properties. The amino acid change p.Arg357Trp in CYP21A2 is predicted as conserved by GERP++ and PhyloP across 100 vertebrates. Multiple lines of computational evidence Polyphen - Possibly Damaging, SIFT - Damaging, and MutationTaster - Disease causing automatic predict a damaging effect on protein structure and function for this variant. For these reasons, this variant has been classified as Pathogenic. -
Pathogenic, criteria provided, single submitter	clinical testing	Greenwood Genetic Center Diagnostic Laboratories, Greenwood Genetic Center	Dec 21, 2023	PS3, PM1, PM3_Very Strong, PM5, PP3 -
not provided, no classification provided	literature only	GeneReviews	-	- -
Pathogenic, no assertion criteria provided	clinical testing	Lifecell International Pvt. Ltd	-	- -
Pathogenic, criteria provided, single submitter	clinical testing	Myriad Genetics, Inc.	Dec 20, 2019	NM_000500.7(CYP21A2):c.1069C>T(R357W) is classified as pathogenic in the context of congenital adrenal hyperplasia and is associated with the classic form of the disease. Sources cited for classification include the following: PMID 21134444, 10496074 and 23359698. Classification of NM_000500.7(CYP21A2):c.1069C>T(R357W) 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. -
Pathogenic, criteria provided, single submitter	clinical testing	Juno Genomics, Hangzhou Juno Genomics, Inc	-	PM3_VeryStrong+PM2_Supporting+PP4 -
Pathogenic, criteria provided, single submitter	clinical testing	Center for Genomic Medicine, King Faisal Specialist Hospital and Research Center	Dec 10, 2024	PS3, PM1, PM2, PM3, PM5, PP3, PP5 -
Pathogenic, criteria provided, single submitter	clinical testing	Fulgent Genetics, Fulgent Genetics	Mar 15, 2022	- -

not provided

Pathogenic:5

Pathogenic, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Oct 31, 2022	This sequence change replaces arginine, which is basic and polar, with tryptophan, which is neutral and slightly polar, at codon 357 of the CYP21A2 protein (p.Arg357Trp). The frequency data for this variant in the population databases (gnomAD) is considered unreliable due to the presence of homologous sequence, such as pseudogenes or paralogs, in the genome. This missense change has been observed in individual(s) with classic salt-wasting, simple virilizing, and non-classic congenital adrenal hyperplasia due to 21-hydroxylase deficiency (PMID: 2303461, 23359698, 25227725, 26804566). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. This variant is also known as R356W. ClinVar contains an entry for this variant (Variation ID: 12152). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is expected to disrupt CYP21A2 protein function. Experimental studies have shown that this missense change affects CYP21A2 function (PMID: 2303461, 21134444). For these reasons, this variant has been classified as Pathogenic. -
Pathogenic, criteria provided, single submitter	clinical testing	Clinical Genetics Laboratory, Skane University Hospital Lund	Aug 18, 2022	- -
Pathogenic, criteria provided, single submitter	clinical testing	Quest Diagnostics Nichols Institute San Juan Capistrano	Jun 29, 2023	The CYP21A2 c.1069C>T (p.Arg357Trp) variant (also known as R357W or R356W) has been reported in the published literature as being associated with a salt-wasting CAH phenotype (PMIDs: 14513879 (2003), 23359698 (2013), 26206692 (2015), 26804566 (2016)). Functional studies show that this variant causes loss of enzymatic activity (PMIDs: 2303461 (1990), 14513879 (2003)). The frequency of this variant in the general population, 0.00015 (3/19676 chromosomes (Genome Aggregation Database, http://gnomad.broadinstitute.org)), is uninformative in the assessment of its pathogenicity. Based on the available information, this variant is classified as pathogenic. -
Pathogenic, criteria provided, single submitter	clinical testing	Clinical Genetics and Genomics, Karolinska University Hospital	Sep 17, 2015	- -
Pathogenic, criteria provided, single submitter	clinical testing	Athena Diagnostics	Jun 29, 2023	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. In some published literature, this variant is referred to as p.Arg356Trp. 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. Several studies show this variant causes loss of enzymatic activity (PMID: 26206692, 21329531, 14513879). -

CYP21A2-related disorder

Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Apr 17, 2023

The CYP21A2 c.1069C>T variant is predicted to result in the amino acid substitution p.Arg357Trp. In the literature, this variant is also referred to as R356W. This variant has been reported to be associated with salt-wasting (SW) congenital adrenal hyperplasia (CAH) (see for example at Finkielstain et al. 2011. PubMed ID: 20926536; New et al. 2013. PubMed ID: 23359698). This is a common deleterious variant, which likely originated from the pseudogene CYP21A1P via gene conversion. This variant is interpreted as pathogenic. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_addAF

Pathogenic

0.22

BayesDel_noAF

Uncertain

0.080

CADD

Uncertain

DANN

Pathogenic

1.0

Eigen

Uncertain

0.50

Eigen_PC

Uncertain

0.41

FATHMM_MKL

Benign

0.42

M_CAP

Pathogenic

0.76

MetaRNN

Pathogenic

0.97

D;D;D;D

MetaSVM

Uncertain

0.28

PrimateAI

Uncertain

0.79

PROVEAN

Pathogenic

-7.0

D;.;D;.

REVEL

Pathogenic

0.68

Sift

Pathogenic

0.0

D;.;D;.

Sift4G

Uncertain

0.048

D;.;T;.

Polyphen

1.0

D;D;.;D

Vest4

0.92

MutPred

0.94

Loss of disorder (P = 0.0366);Loss of disorder (P = 0.0366);.;Loss of disorder (P = 0.0366);

MVP

0.98

MPC

3.5

ClinPred

0.99

GERP RS

4.4

gMVP

0.92

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.13

Details are displayed if max score is > 0.2

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

Publications

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over