NM_000500.9:c.713T>A

Variant names:

Variant summary

Our verdict is Likely pathogenic. Variant got 9 ACMG points: 9P and 0B. PM1PM2PP3_StrongPP5

The NM_000500.9(CYP21A2):c.713T>A(p.Val238Glu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000248 in 1,613,928 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 Conflicting classifications of pathogenicity (no stars).

Frequency

Genomes: 𝑓 0.000013 ( 0 hom., cov: 31)

Exomes 𝑓: 0.0000014 ( 0 hom. )

Consequence

CYP21A2
NM_000500.9 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:4U:2

Conservation

PhyloP100: 1.71

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 Likely_pathogenic. Variant got 9 ACMG points.

PM1

In a helix (size 22) in uniprot entity CP21A_HUMAN there are 8 pathogenic changes around while only 1 benign (89%) in NM_000500.9

PM2

Very rare variant in population databases, with high coverage;

PP3

MetaRNN computational evidence supports a deleterious effect, 0.986

PP5

Variant 6-32039810-T-A is Pathogenic according to our data. Variant chr6-32039810-T-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 12173.We mark this variant Likely_pathogenic, oryginal submissions are: {Likely_pathogenic=2, Uncertain_significance=2, Pathogenic=2}. Variant chr6-32039810-T-A is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CYP21A2	NM_000500.9 link	c.713T>A	p.Val238Glu	missense_variant	Exon 6 of 10	ENST00000644719.2	NP_000491.4	P08686Q16874Q08AG9
CYP21A2	NM_001128590.4 link	c.623T>A	p.Val208Glu	missense_variant	Exon 5 of 9		NP_001122062.3	P08686Q08AG9
CYP21A2	NM_001368143.2 link	c.308T>A	p.Val103Glu	missense_variant	Exon 6 of 10		NP_001355072.1
CYP21A2	NM_001368144.2 link	c.308T>A	p.Val103Glu	missense_variant	Exon 5 of 9		NP_001355073.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CYP21A2	ENST00000644719.2 link	c.713T>A	p.Val238Glu	missense_variant	Exon 6 of 10		NM_000500.9	ENSP00000496625.1		Q16874

Frequencies

GnomAD3 genomes

AF:

0.0000131

AC:

AN:

152126

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000483

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00

Gnomad OTH

AF:

0.00

GnomAD4 exome

AF:

0.00000137

AC:

AN:

1461684

Hom.:

Cov.:

AF XY:

0.00000138

AC XY:

AN XY:

727102

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.0000252

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

8.99e-7

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

AF:

0.0000131

AC:

AN:

152244

Hom.:

Cov.:

AF XY:

0.0000134

AC XY:

AN XY:

74448

show subpopulations

Gnomad4 AFR

AF:

0.0000481

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.00

Gnomad4 OTH

AF:

0.00

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:4Uncertain:2

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

not provided

Pathogenic:2Uncertain:1

May 23, 2017

Clinical Genetics and Genomics, Karolinska University Hospital

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Oct 31, 2022

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change replaces valine, which is neutral and non-polar, with glutamic acid, which is acidic and polar, at codon 238 of the CYP21A2 protein (p.Val238Glu). 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. The c.713T>A (p.Val238Glu) variant alone has been observed in an individual with classic salt-wasting congenital adrenal hyperplasia due to 21-hydroxylase deficiency (PMID: 26278268). It also frequently co-occurs with the c.710T>A (p.Ile237Asn) and c.719T>A (p.Met240Lys) variants in cis (on the same chromosome), which is known as the c.[710T>A;713T>A;719T>A] haplotype, E6 cluster, or CL6. This haplotype has been reported in the literature as homozygous or in combination with other CYP21A2 variants in individual(s) affected with classic salt-wasting, simple virilizing, and non-classic congenital adrenal hyperplasia due to 21-hydroxylase deficiency (PMID: 12915679, 1644925, 23359698, 26804566). This variant is also known as p.V237E. ClinVar contains an entry for this variant (Variation ID: 12173). 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. The c.713T>A (p.Val238Glu) variant alone affects CYP21A2 protein function, and the c.[710T>A;713T>A;719T>A] haplotype has been reported to abolish enzyme activity (PMID: 15623806). In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. -

Mar 28, 2021

Quest Diagnostics Nichols Institute San Juan Capistrano

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Classic congenital adrenal hyperplasia due to 21-hydroxylase deficiency

Pathogenic:1Uncertain:1

May 22, 2022

3billion

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The variant is observed at an extremely low frequency in the gnomAD v2.1.1 dataset (total allele frequency: <0.001%). Same nucleotide change resulting in same amino acid change has been previously reported to be associated with CYP21A2 related disorder (ClinVar ID: VCV000012173 / PMID: 26278268). Therefore, this variant is classified as pathogenic according to the recommendation of ACMG/AMP guideline. -

Dec 10, 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

PS3, PM1, PM2, PM3, PP3 -

Congenital adrenal hyperplasia

Pathogenic:1

Nov 03, 2024

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

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Variant summary: CYP21A2 c.713T>A (p.Val238Glu) results in a non-conservative amino acid change in the encoded protein sequence. Three of five in-silico tools predict a damaging effect of the variant on protein function. The frequency data for this variant in gnomAD is considered unreliable, as metrics indicate poor data quality at this position. p.V238E is found to be part of a recurrent cluster of 3 variants (I237N, V238E and M240K), which belongs to a group of common, pseudogene-derived mutations that are found in patients with classical CAH. This cluster of 3 variants is assumed to be transferred together from the CYP21A1P pseudogene to CYP21A2 in a continuous stretch of DNA (Robins_2005), and has been reported in the literature in multiple individuals affected with Congenital Adrenal Hyperplasia (e.g. Higashi_1991, Barbat_1995, Chang_2011, Kirac_2014, Essawi_2020, Wang_2021, Liu_2023, Faradz_2023). Nevertheless, p.V238E has also been reported in the literature to occur in isolation in individuals affected with Congenital Adrenal Hyperplasia (e.g. Forouzanfar_2015, Fernandez_2020). These data indicate that the variant is likely to be associated with disease. Furthermore, experimental evidence evaluating an impact on protein function demonstrated that the p.V238E variant alone abolishes enzyme function and is thus a null mutation (Robins_2005). The following publications have been ascertained in the context of this evaluation (PMID: 7749410, 32616876, 21117955, 32614782, 32289882, 26278268, 1869518, 25227725, 16430727, 15623806, 2249999, 33864926, 37699373, 36726778). Four submitters have cited clinical-significance assessments for this variant to ClinVar after 2014 and classified the variant as pathogenic (n=2) and VUS (n=2). Based on the evidence outlined above, the variant was classified as likely 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

Uncertain

0.98

Eigen

Benign

-0.16

Eigen_PC

Benign

-0.30

FATHMM_MKL

Benign

0.17

M_CAP

Uncertain

0.22

MetaRNN

Pathogenic

0.99

D;D;D;D

MetaSVM

Benign

-0.60

PrimateAI

Benign

0.47

PROVEAN

Uncertain

-3.2

D;.;D;.

REVEL

Uncertain

0.44

Sift

Benign

0.043

D;.;D;.

Sift4G

Benign

0.097

T;.;T;.

Polyphen

0.83

P;P;.;P

Vest4

0.90

MutPred

0.91

Gain of disorder (P = 0.0013);Gain of disorder (P = 0.0013);.;Gain of disorder (P = 0.0013);

MVP

1.0

MPC

1.5

ClinPred

0.96

GERP RS

4.1

gMVP

0.86

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

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