VCV000012155.41 - ClinVar

NM_000500.9(CYP21A2):c.293-13C>G

Interpretation:: Conflicting interpretations of pathogenicity
Pathogenic(19); Likely pathogenic(1); Uncertain significance(1)
Review status:: criteria provided, conflicting interpretations
Submissions:: 26
First in ClinVar:: Apr 4, 2013
Most recent Submission:: Oct 6, 2023
Last evaluated:: May 3, 2023
Accession:: VCV000012155.41
Variation ID:: 12155
Description:: single nucleotide variant

NM_000500.9(CYP21A2):c.293-13C>G

Allele ID

27194

Variant type

single nucleotide variant

Variant length

1 bp

Cytogenetic location

6p21.33

Genomic location

6: 32039081 (GRCh38) GRCh38 UCSC

6: 32006858 (GRCh37) GRCh37 UCSC

HGVS

Nucleotide	Protein	Molecular consequence
NM_000500.9:c.293-13C>G MANE Select		intron variant
NM_001128590.4:c.203-13C>G		intron variant
NM_001368143.2:c.-126C>G		5 prime UTR
NM_001368144.2:c.-126C>G		5 prime UTR
NC_000006.12:g.32039081C>G
NC_000006.11:g.32006858C>G
NG_007941.3:g.5777C>G
NG_045215.1:g.1310C>G
LRG_829:g.5777C>G
LRG_829t1:c.293-13C>G

... more HGVS ... less HGVS

Protein change

Other names

Canonical SPDI

NC_000006.12:32039080:C:G

Functional consequence

sequence_variant_affecting_splicing [Sequence Ontology SO:1000071]

Global minor allele frequency (GMAF)

0.34824 (C)

Allele frequency

1000 Genomes Project 0.00100

Links

ClinGen: CA341185

OMIM: 613815.0006

dbSNP: rs6467

VarSome

Aggregate interpretations per condition

Interpreted condition	Interpretation	Number of submissions	Review status	Last evaluated	Variation/condition record
Classic congenital adrenal hyperplasia due to 21-hydroxylase deficiency	Conflicting interpretations of pathogenicity	16	criteria provided, conflicting interpretations	May 3, 2023	RCV000012939.30
Inborn genetic diseases	Pathogenic	1	criteria provided, single submitter	Apr 22, 2016	RCV000624227.3
not provided	Pathogenic	7	criteria provided, multiple submitters, no conflicts	Dec 17, 2022	RCV000711376.17
Adrenal hyperplasia	Pathogenic	1	criteria provided, single submitter	Jan 8, 2020	RCV001263256.2
Abnormality of the female genitalia	Pathogenic	1	criteria provided, single submitter	Oct 19, 2018	RCV002227033.2

Clinical features observed in individuals with this variant

Gene	OMIM	ClinGen Gene Dosage Sensitivity Curation		Variation viewer	Related variants
Gene	OMIM	HI score Help	TS score Help	Variation viewer	Within gene	All
CYP21A2		-	-	GRCh38 GRCh38 GRCh38 GRCh38 GRCh38 GRCh38 GRCh37	15	311
LOC106780800	-	-	-	GRCh38 GRCh38	-	269

Submitted interpretations and evidence

Interpretation (Last evaluated)	Review status (Assertion criteria)	Condition (Inheritance)	Submitter	More information
Pathogenic (Jan 15, 2019)	criteria provided, single submitter (ICSLVariantClassificationCriteria RUGD 01 April 2020) Method: clinical testing	- Classic congenital adrenal hyperplasia due to 21-hydroxylase deficiency Affected status: unknown Allele origin: unknown	Illumina Laboratory Services, Illumina Accession: SCV001451452.1 First in ClinVar: Dec 22, 2020 Last updated: Dec 22, 2020	Publications: PubMed (5) PubMed: 1644925‚ 24904866‚ 25630015‚ 26206692‚ 2845408 Comment: The CYP21A2 c.293-13C>G variant is an intronic variant. Across a selection of the available literature, this variant has been reported in a homozygous state in … (more) The CYP21A2 c.293-13C>G variant is an intronic variant. Across a selection of the available literature, this variant has been reported in a homozygous state in at least 13 individuals with congenital adrenal hyperplasia due to 21-hydroxylase deficiency and in a compound heterozygous state in at least 48 patients (Speiser et al. 1992; Yoo et al. 2013; Hong et al. 2015; Mohamed et al. 2015). In several families, presumably unaffected parents were identified to be heterozygous carriers of the c.293-13C>G variant. This variant is reported at a frequency of 0.003896 in the Ashkenazi Jewish population from the Genome Aggregation Database. Functional studies in COS-7 cells showed absent CYP21A2 activity for this variant (Higashi et al. 1988). Further, the c.293-13C>G variant was shown to result in abnormal splicing, producing a frameshift which results in premature truncation of the protein. Based on the collective evidence, the c.293-13C>G variant is pathogenic for congenital adrenal hyperplasia due to 21-hydroxylase deficiency. (less)
Pathogenic (Feb 05, 2021)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	- not provided Affected status: yes Allele origin: germline	Greenwood Genetic Center Diagnostic Laboratories, Greenwood Genetic Center Accession: SCV002051558.2 First in ClinVar: Jan 08, 2022 Last updated: Feb 11, 2022	Comment: PS3, PS4
Pathogenic (Oct 19, 2018)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	- Abnormality of the female genitalia Affected status: yes Allele origin: germline	Institute of Human Genetics, University Hospital Muenster Accession: SCV002506419.1 First in ClinVar: May 07, 2022 Last updated: May 07, 2022	Comment: ACMG categories: PS3,PM2,PM3,PP1,PP4,PP5 Number of individuals with the variant: 1 Clinical Features: Clitoral hypertrophy (present) , Abnormality of the genitourinary system (present) , Abnormality of the female genitalia (present) , Hypoplastic female external genitalia (present) Zygosity: 1 Homozygote
Pathogenic (Apr 22, 2016)	criteria provided, single submitter (Ambry exome assertion method (8-5-2015)) Method: clinical testing	- Inborn genetic diseases Affected status: yes Allele origin: germline	Ambry Genetics Accession: SCV000741505.3 First in ClinVar: Apr 15, 2018 Last updated: Jan 07, 2023	Publications: PubMed (7) PubMed: 27041116‚ 25227725‚ 25501839‚ 26804566‚ 23359698‚ 2845408‚ 28392195 Observation 1: Number of individuals with the variant: 1 Clinical Features: Persistent lactic acidosis (present) , Congenital adrenal hyperplasia (present) , Growth delay (present) , Patent ductus arteriosus (present) , Atrial septal defect (present) , Right … (more) Persistent lactic acidosis (present) , Congenital adrenal hyperplasia (present) , Growth delay (present) , Patent ductus arteriosus (present) , Atrial septal defect (present) , Right ventricular hypertrophy (present) , Right ventricular dilatation (present) , Aortic root dilatation (present) , Aortic regurgitation (present) , Cryptorchidism (present) , Synophrys (present) , Delayed speech and language development (present) , Abnormality of brain morphology (present) , Neonatal respiratory distress (present) , Microcephaly (present) , Pulmonary arterial hypertension (present) , Long eyelashes (present) , Short stature (present) , Downturned corners of mouth (present) , Decreased body weight (present) , Failure to thrive (present) (less) Sex: male Ethnicity/Population group: Hispanic/Guatemalan Observation 2: Number of individuals with the variant: 1 Sex: female Ethnicity/Population group: Caucasian Observation 3: Number of individuals with the variant: 1 Clinical Features: Congenital adrenal hyperplasia (present) , Hematuria (present) , Growth hormone deficiency (present) , Frontal bossing (present) , Failure to thrive (present) , Microcephaly (present) , … (more) Congenital adrenal hyperplasia (present) , Hematuria (present) , Growth hormone deficiency (present) , Frontal bossing (present) , Failure to thrive (present) , Microcephaly (present) , Short stature (present) , High, narrow palate (present) , Global developmental delay (present) , Spotty hyperpigmentation (present) , Abnormality of the posterior pituitary (present) , Cryptorchidism (present) (less) Sex: male Ethnicity/Population group: Caucasian/Bulgarian
Pathogenic (Apr 05, 2022)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	- not provided Affected status: unknown Allele origin: germline	PerkinElmer Genomics Accession: SCV002018113.2 First in ClinVar: Nov 29, 2021 Last updated: Mar 11, 2023
Pathogenic (Mar 15, 2023)	criteria provided, single submitter (LabCorp Variant Classification Summary - May 2015) Method: clinical testing	- Classic congenital adrenal hyperplasia due to 21-hydroxylase deficiency Affected status: unknown Allele origin: germline	Women's Health and Genetics/Laboratory Corporation of America, LabCorp Accession: SCV003922698.1 First in ClinVar: May 13, 2023 Last updated: May 13, 2023	Publications: PubMed (3) PubMed: 2845408‚ 17275379‚ 23359698 Comment: Variant summary: CYP21A2 c.293-13C>G alters a non-conserved nucleotide located close to a canonical splice site and therefore could affect mRNA splicing, leading to a significantly … (more) Variant summary: CYP21A2 c.293-13C>G alters a non-conserved nucleotide located close to a canonical splice site and therefore could affect mRNA splicing, leading to a significantly altered protein sequence. Several computational tools predict a significant impact on normal splicing: Two predict the variant weakens a 3' acceptor site, and one predicts the variant abolishes a 3' acceptor site. At least one publication reports experimental evidence that this variant affects mRNA splicing (e.g., Higashi_1988). The variant allele was found at a frequency of 0.0023 in 221616 control chromosomes (gnomAD v2.1, Exomes cohort), however, this allele frequency data may be unreliable due to reported possible pseudogene overlap. c.293-13C>G has been reported in the literature in numerous homozygous and compound heterozygous individuals affected with Congenital Adrenal Hyperplasia/Salt Wasting, presenting with salt-wasting, simple virilizing, and non-classical phenotypes (e.g., Wilson_2007, New_2013). 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, finding that COS cells transfected with the variant displayed undetectable steroid 21-hydroxylase activity (e.g., Higashi_1988). Nineteen ClinVar submitters (evaluation after 2014) have cited the variant, with eighteen submitters classifying the variant as pathogenic and only one submitter classifying the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as pathogenic. (less)
Pathogenic (May 03, 2023)	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	Baylor Genetics Accession: SCV001524846.3 First in ClinVar: Mar 22, 2021 Last updated: Oct 06, 2023
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: paternal	Institute of Human Genetics, Klinikum rechts der Isar Accession: SCV000680184.1 First in ClinVar: Feb 08, 2018 Last updated: Feb 08, 2018	Zygosity: 1 Compound Heterozygote Sex: female Tissue: blood
Pathogenic (Jul 24, 2015)	criteria provided, single submitter (EGL Classification Definitions 2015) Method: clinical testing	- not provided Affected status: unknown Allele origin: germline	Eurofins Ntd Llc (ga) Accession: SCV000330929.4 First in ClinVar: Dec 06, 2016 Last updated: Dec 15, 2018	Publications: PubMed (1) PubMed: 25630015 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: 17 Zygosity: 1 Homozygote, 15 Single Heterozygote Sex: mixed
Pathogenic (Oct 31, 2018)	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: SCV000893711.1 First in ClinVar: Mar 31, 2019 Last updated: Mar 31, 2019	Publications: PubMed (1) PubMed: 25741868 pmc: 4544753 pmc: 4544753 DOI: 10.1038/gim.2015.30 DOI: 10.1038/gim.2015.30
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: SCV001137077.1 First in ClinVar: Jan 09, 2020 Last updated: Jan 09, 2020
Pathogenic (Dec 20, 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: SCV001194142.2 First in ClinVar: Apr 06, 2020 Last updated: Jul 03, 2020	Publications: PubMed (2) PubMed: 1644925‚ 2845408 Comment: NM_000500.7(CYP21A2):c.293-13C>G is classified as pathogenic in the context of congenital adrenal hyperplasia and is associated with the classic form of the disease. Sources cited for … (more) NM_000500.7(CYP21A2):c.293-13C>G 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 1644925 and 2845408. Classification of NM_000500.7(CYP21A2):c.293-13C>G 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 (Jan 08, 2020)	criteria provided, single submitter (NYGC Assertion Criteria 2020) Method: clinical testing	- Adrenal hyperplasia (Autosomal recessive inheritance) Affected status: yes Allele origin: germline	New York Genome Center Study: CSER-NYCKidSeq Accession: SCV001441293.1 First in ClinVar: Nov 06, 2020 Last updated: Nov 06, 2020	Zygosity: 1 Single Heterozygote Secondary finding: no
Likely pathogenic (-)	criteria provided, single submitter (ACGS Guidelines, 2016) Method: clinical testing	- Classic congenital adrenal hyperplasia due to 21-hydroxylase deficiency Affected status: yes Allele origin: germline	Genomics England Pilot Project, Genomics England Accession: SCV001760175.2 First in ClinVar: Jul 27, 2021 Last updated: Sep 03, 2023
Pathogenic (Jul 21, 2021)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	- Classic congenital adrenal hyperplasia due to 21-hydroxylase deficiency Affected status: yes Allele origin: unknown	Institute of Human Genetics, University of Leipzig Medical Center Accession: SCV001950083.1 First in ClinVar: Oct 02, 2021 Last updated: Oct 02, 2021	Comment: This variant was identified as compound heterozygous with NM_000500.9:c.?_939+50del.
Uncertain significance (Jan 01, 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: maternal	Provincial Medical Genetics Program of British Columbia, University of British Columbia Accession: SCV002320847.1 First in ClinVar: Apr 08, 2022 Last updated: Apr 08, 2022	Sex: male
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: SCV002521128.1 First in ClinVar: Jun 03, 2022 Last updated: Jun 03, 2022	Publications: PubMed (3) PubMed: 26206692‚ 24904866‚ 25630015 Comment: The variant is observed at an extremely low frequency in the gnomAD v2.1.1 dataset (total allele frequency: 0.220%). However, frequency data for this variant in … (more) The variant is observed at an extremely low frequency in the gnomAD v2.1.1 dataset (total allele frequency: 0.220%). 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. In silico tools predict the variant to alter splicing and produce an abnormal transcript (SpliceAI: 0.75). The variant has been reported to be in trans with a pathogenic variant as either compound heterozygous or homozygous in at least 2 similarly affected unrelated individuals (PMID: 24904866, 25630015, 26206692). Therefore, this variant is classified as pathogenic according to the recommendation of ACMG/AMP guideline. (less) Clinical Features: Ambiguous genitalia (present) , Dehydration (present) , Hyponatremia (present) , Hyperkalemia (present) , Vomiting (present) , Elevated circulating 17-hydroxyprogesterone concentration (present) , Short stature (present) Zygosity: 1 Homozygote
Pathogenic (Apr 22, 2022)	criteria provided, single submitter (Athena Diagnostics Criteria) Method: clinical testing	- not provided Affected status: unknown Allele origin: unknown	Athena Diagnostics Inc Accession: SCV000841739.3 First in ClinVar: Oct 20, 2018 Last updated: Dec 31, 2022	Publications: PubMed (20) PubMed: 12915679‚ 12788880‚ 1644925‚ 1985465‚ 33604243‚ 32959514‚ 32289882‚ 31586465‚ 12213891‚ 25353971‚ 23769969‚ 25630015‚ 26985347‚ 25501839‚ 26804566‚ 19420818‚ 17275379‚ 18381579‚ 2845408‚ 23359698 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 (Genome Aggregation Database (gnomAD), Cambridge, MA (URL: http://gnomad.broadinstitute.org)). In some published literature, this variant is referred to by nucleotide 655 or 656, and also called the intron 2 G, I2G, or I2 splice variant. 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. This variant leads to aberrant RNA splicing and the resulting enzyme has little or no activity (PMID: 2845408). (less)
Pathogenic (Apr 22, 2022)	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: SCV001469963.3 First in ClinVar: Jan 26, 2021 Last updated: Dec 31, 2022	Publications: PubMed (20) PubMed: 12915679‚ 12788880‚ 1644925‚ 1985465‚ 33604243‚ 32959514‚ 32289882‚ 31586465‚ 12213891‚ 25353971‚ 23769969‚ 25630015‚ 26985347‚ 25501839‚ 26804566‚ 19420818‚ 17275379‚ 18381579‚ 2845408‚ 23359698 Comment: This variant has been reported in at least one symptomatic individual. It occurs in multiple cases with a lone recessive pathogenic/likely pathogenic variant in the … (more) This variant has been reported in at least one symptomatic individual. It occurs in multiple cases with a lone recessive pathogenic/likely pathogenic variant in the same gene. The variant is predicted to negatively affect a known splice site and was shown to be damaging to protein function(s) relevant to disease mechanism. (less)
Pathogenic (Dec 17, 2022)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	- not provided Affected status: yes Allele origin: germline	Al Jalila Children's Genomics Center, Al Jalila Childrens Speciality Hospital Accession: SCV002818261.1 First in ClinVar: Jan 07, 2023 Last updated: Jan 07, 2023
Pathogenic (Oct 31, 2022)	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015)) Method: clinical testing	- not provided Affected status: unknown Allele origin: germline	Invitae Accession: SCV002243459.2 First in ClinVar: Mar 28, 2022 Last updated: Feb 07, 2023	Publications: PubMed (2) PubMed: 20080860‚ 30995443 Comment: This sequence change falls in intron 2 of the CYP21A2 gene. It does not directly change the encoded amino acid sequence of the CYP21A2 protein. … (more) This sequence change falls in intron 2 of the CYP21A2 gene. It does not directly change the encoded amino acid sequence of the CYP21A2 protein. 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 variant has been observed in individual(s) with classic salt-wasting, simple virilizing, and non-classic congenital adrenal hyperplasia due to 21-hydroxylase deficiency (PMID: 20080860, 30995443). 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 IVS2-13A/C>G, I2G, c.293-13A/C>G, In2G. ClinVar contains an entry for this variant (Variation ID: 12155). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. For these reasons, this variant has been classified as Pathogenic. (less)
Pathogenic (Aug 01, 2003)	no assertion criteria provided Method: literature only	- ADRENAL HYPERPLASIA, CONGENITAL, DUE TO 21-HYDROXYLASE DEFICIENCY Affected status: not provided Allele origin: germline	OMIM Accession: SCV000033181.1 First in ClinVar: Apr 04, 2013 Last updated: Apr 04, 2013	Publications: PubMed (11) PubMed: 2845408‚ 2325662‚ 1985465‚ 8081391‚ 5804199‚ 7096533‚ 1644925‚ 7635470‚ 8968761‚ 12788880‚ 12915679 Miller, W. L. Personal (more...) Miller, W. L. Personal Communication. 1996. San Francisco, Calif. Comment on evidence: The most frequent nondeletional mutation found in patients with classic congenital adrenal hyperplasia due to 21-hydroxylase deficiency (201910) is an A-to-G transition at position -2 … (more) The most frequent nondeletional mutation found in patients with classic congenital adrenal hyperplasia due to 21-hydroxylase deficiency (201910) is an A-to-G transition at position -2 in the acceptor splice site of intron 2. As a result of the mutation, an aberrant splice acceptor site is activated 7 bases upstream of the mutation (Higashi et al., 1988). As pointed out by Miller (1996), this mutation, located in intron 2, is 13 bases (not 2) from the splice acceptor site of exon 3. According to the nucleotide numbering system of Higashi et al. (1988), it is residue 655. Miller (1996) noted that this base is normally polymorphic, being either C or A with roughly equal frequency in the normal population. Either a C-to-G or A-to-G mutation at nucleotide -13 causes the severe 21-OH deficiency. This mutation has been detected in patients affected with either the salt-wasting or simple virilizing forms of the disorder (Owerbach et al., 1990; Mornet et al., 1991). White et al. (1994) reported that this mutation represents 22% of the salt-wasting cases, 25% of the simple virilizing cases, and 12% of the nonclassic cases. As reported by Hirschfeld and Fleshman (1969) and Pang et al. (1982), the Yupik Eskimos of western Alaska have the world's highest prevalence of HLA-linked classic congenital adrenal hyperplasia due to steroid 21-hydroxylase deficiency. The frequency was estimated to be between 1 in 282 and 1 in 490 liveborn infants. Studying 4 patients from 3 apparently unrelated Eskimo families residing in geographically distant villages, Speiser et al. (1992) found that all were homozygous for a substitution of G for A at base 656 in the second intron. They concluded that allele-specific hybridization should be an efficient means of prenatal diagnosis in this isolated population. In the Spanish population, Ezquieta et al. (1995) found this splicing mutation in 30% of 41 mutant chromosomes, making it the most frequent cause of severe CAH in this population. They stated the mutation as an A-to-G change at nucleotide 655 of their clone. During the course of genetic analysis of CYP21 mutations in CAH families, Day et al. (1996) noticed a number of relatives genotyped as nucleotide 656G homozygotes who showed no clinical signs of disease. They proposed that the putative asymptomatic nucleotide 656G/G individuals are incorrectly typed due to a dropout of 1 haplotype during PCR amplification of CYP21. They recommended that for prenatal diagnosis, microsatellite typing be used as a supplement to CYP21 genotyping in order to resolve ambiguities at nucleotide 656. Lee et al. (2003) noted that approximately 75% of defective CYP21 genes that cause CAH are generated through intergenic recombination, termed apparent gene conversion, from the neighboring CYP21P pseudogene. Among them, the common intron 2 splice site mutation, which Lee et al. (2003) designated IVS2-12A/C-G, is believed to be derived from this mechanism and is the most prevalent case among all ethnic groups. However, mutation of 707-714delGAGACTAC (613815.0015) rarely exists alone, although this locus is 53 nucleotides away from IVS2-12A/C-G. From the molecular characterization of the mutation of IVS2-12A/C-G combined with 707-714delGAGACTAC in patients with congenital adrenal hyperplasia, Lee et al. (2003) found that it appeared to be in a 3.2- rather than a 3.7-kb fragment generated by Taq I digestion in a PCR product of the CYP21 gene. Interestingly, the 5-prime end region of such a CYP21 haplotype had CYP21P-specific sequences. The authors concluded that the coexistence of these 2 mutations is caused by deletion of the CYP21P, XA (TNXA; see 600985), RP2 (pseudogene of STK19, 604977), and C4B (120820) genes and intergenic recombination in the C4-CYP21 repeat module. Among 370 unrelated alleles from patients in the Netherlands with 21-hydroxylase deficiency, Stikkelbroeck et al. (2003) found this to be the most common point mutation, occurring in 28.1% of alleles. They referred to the mutation as I2G (IVS2-13A/C-G; 656A/C-G). (less)
Pathogenic (-)	no assertion criteria provided 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: SCV001482472.2 First in ClinVar: Mar 07, 2021 Last updated: Mar 07, 2021	Comment: This variant present in Intron 2 of the CYP21A2 gene c.293-13A/C>G (NM_000500.7). This variant was observed in a proband with increased level of 17-OHP enzyme … (more) This variant present in Intron 2 of the CYP21A2 gene c.293-13A/C>G (NM_000500.7). This variant was observed in a proband with increased level of 17-OHP enzyme (>303.7nmol/L) which was screened for advanced newborn screening with confirmatory genetic reflex testing at lifecell diagnostics. This variant has a minor allele frequency of 0.1988% and 0.2261% in 1000 genomes and gnomAD Exomes databases respectively. This variant is characterized by the substitution of A or C nucleotide at 13 bp before the end of intron 2 to G, and activates a cryptic upstream 3' splice acceptor site and causing aberrant splicing (New et al., 2013)This variant has been reported for 21-hydroxylase deficiency (Billerbeck AE et al., 2002 PMID: 12213891, Higashi et al., 1988 PMID: 2845408, Speiser et al., 1992 PMID: 1644925). (less) Indication for testing: Decreased level of 17-OHP enzyme (>303 nM/L) Zygosity: 1 Homozygote Testing laboratory: GTRL000507720 Testing laboratory interpretation: Pathogenic
pathologic (Aug 29, 2013)	no assertion criteria provided Method: curation	- 21-Hydroxylase-Deficient Congenital Adrenal Hyperplasia Affected status: not provided Allele origin: not provided	GeneReviews Accession: SCV000086795.2 First in ClinVar: Oct 01, 2013 Last updated: Sep 03, 2023	Comment: Converted during submission to Pathogenic.
pathologic (Aug 29, 2013)	no assertion criteria provided Method: curation	- 21-Hydroxylase-Deficient Congenital Adrenal Hyperplasia Affected status: not provided Allele origin: not provided	GeneReviews Accession: SCV000086796.1 First in ClinVar: Oct 02, 2013 Last updated: Oct 02, 2013	Comment: Converted during submission to Pathogenic.
not provided (-)	no assertion provided Method: phenotyping only	- Classic congenital adrenal hyperplasia due to 21-hydroxylase deficiency Affected status: unknown Allele origin: unknown	GenomeConnect, ClinGen Accession: SCV002074917.1 First in ClinVar: Feb 11, 2022 Last updated: Feb 11, 2022	Comment: Variant interpreted as Pathogenic and reported on 11-12-2018 by Lab or GTR ID 500068. GenomeConnect assertions are reported exactly as they appear on the patient-provided … (more) Variant interpreted as Pathogenic and reported on 11-12-2018 by Lab or GTR ID 500068. GenomeConnect assertions are reported exactly as they appear on the patient-provided report from the testing laboratory. GenomeConnect staff make no attempt to reinterpret the clinical significance of the variant. (less) Clinical Features: Abnormality of the amniotic fluid (present) , Decreased fetal movement (present) , Abnormal delivery (present) , Pregnancy history (present) , Abnormal placenta morphology (present) , … (more) Abnormality of the amniotic fluid (present) , Decreased fetal movement (present) , Abnormal delivery (present) , Pregnancy history (present) , Abnormal placenta morphology (present) , Maternal teratogenic exposure (present) , Premature birth (present) , Abnormality of the umbilical cord (present) , Adrenal hyperplasia (present) , Myopia (present) , Anxiety (present) , Depression (present) , Increased susceptibility to fractures (present) , Abnormal sex determination (present) , Abnormality of the female genitalia (present) , Abnormality of reproductive system physiology (present) , Abnormal number of teeth (present) , Tooth malposition (present) (less) Age: 30-39 years Sex: female Testing laboratory: Mayo Clinic Laboratories,Mayo Clinic Date variant was reported to submitter: 2018-11-12 Testing laboratory interpretation: Pathogenic

Comment:

The CYP21A2 c.293-13C>G variant is an intronic variant. Across a selection of the available literature, this variant has been reported in a homozygous state in at least 13 individuals with congenital adrenal hyperplasia due to 21-hydroxylase deficiency and in a compound heterozygous state in at least 48 patients (Speiser et al. 1992; Yoo et al. 2013; Hong et al. 2015; Mohamed et al. 2015). In several families, presumably unaffected parents were identified to be heterozygous carriers of the c.293-13C>G variant. This variant is reported at a frequency of 0.003896 in the Ashkenazi Jewish population from the Genome Aggregation Database. Functional studies in COS-7 cells showed absent CYP21A2 activity for this variant (Higashi et al. 1988). Further, the c.293-13C>G variant was shown to result in abnormal splicing, producing a frameshift which results in premature truncation of the protein. Based on the collective evidence, the c.293-13C>G variant is pathogenic for congenital adrenal hyperplasia due to 21-hydroxylase deficiency.

Comment:

Variant summary: CYP21A2 c.293-13C>G alters a non-conserved nucleotide located close to a canonical splice site and therefore could affect mRNA splicing, leading to a significantly altered protein sequence. Several computational tools predict a significant impact on normal splicing: Two predict the variant weakens a 3' acceptor site, and one predicts the variant abolishes a 3' acceptor site. At least one publication reports experimental evidence that this variant affects mRNA splicing (e.g., Higashi_1988). The variant allele was found at a frequency of 0.0023 in 221616 control chromosomes (gnomAD v2.1, Exomes cohort), however, this allele frequency data may be unreliable due to reported possible pseudogene overlap. c.293-13C>G has been reported in the literature in numerous homozygous and compound heterozygous individuals affected with Congenital Adrenal Hyperplasia/Salt Wasting, presenting with salt-wasting, simple virilizing, and non-classical phenotypes (e.g., Wilson_2007, New_2013). 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, finding that COS cells transfected with the variant displayed undetectable steroid 21-hydroxylase activity (e.g., Higashi_1988). Nineteen ClinVar submitters (evaluation after 2014) have cited the variant, with eighteen submitters classifying the variant as pathogenic and only one submitter classifying the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as pathogenic.

Comment:

NM_000500.7(CYP21A2):c.293-13C>G 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 1644925 and 2845408. Classification of NM_000500.7(CYP21A2):c.293-13C>G 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:

The variant is observed at an extremely low frequency in the gnomAD v2.1.1 dataset (total allele frequency: 0.220%). 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. In silico tools predict the variant to alter splicing and produce an abnormal transcript (SpliceAI: 0.75). The variant has been reported to be in trans with a pathogenic variant as either compound heterozygous or homozygous in at least 2 similarly affected unrelated individuals (PMID: 24904866, 25630015, 26206692). Therefore, this variant is classified as pathogenic according to the recommendation of ACMG/AMP guideline.

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 (Genome Aggregation Database (gnomAD), Cambridge, MA (URL: http://gnomad.broadinstitute.org)). In some published literature, this variant is referred to by nucleotide 655 or 656, and also called the intron 2 G, I2G, or I2 splice variant. 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. This variant leads to aberrant RNA splicing and the resulting enzyme has little or no activity (PMID: 2845408).

Comment:

This variant has been reported in at least one symptomatic individual. It occurs in multiple cases with a lone recessive pathogenic/likely pathogenic variant in the same gene. The variant is predicted to negatively affect a known splice site and was shown to be damaging to protein function(s) relevant to disease mechanism.

Comment:

This sequence change falls in intron 2 of the CYP21A2 gene. It does not directly change the encoded amino acid sequence of the CYP21A2 protein. 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 variant has been observed in individual(s) with classic salt-wasting, simple virilizing, and non-classic congenital adrenal hyperplasia due to 21-hydroxylase deficiency (PMID: 20080860, 30995443). 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 IVS2-13A/C>G, I2G, c.293-13A/C>G, In2G. ClinVar contains an entry for this variant (Variation ID: 12155). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. For these reasons, this variant has been classified as Pathogenic.

Comment:

This variant present in Intron 2 of the CYP21A2 gene c.293-13A/C>G (NM_000500.7). This variant was observed in a proband with increased level of 17-OHP enzyme (>303.7nmol/L) which was screened for advanced newborn screening with confirmatory genetic reflex testing at lifecell diagnostics. This variant has a minor allele frequency of 0.1988% and 0.2261% in 1000 genomes and gnomAD Exomes databases respectively. This variant is characterized by the substitution of A or C nucleotide at 13 bp before the end of intron 2 to G, and activates a cryptic upstream 3' splice acceptor site and causing aberrant splicing (New et al., 2013)This variant has been reported for 21-hydroxylase deficiency (Billerbeck AE et al., 2002 PMID: 12213891, Higashi et al., 1988 PMID: 2845408, Speiser et al., 1992 PMID: 1644925).

Comment:

Variant interpreted as Pathogenic and reported on 11-12-2018 by Lab or GTR ID 500068. GenomeConnect assertions are reported exactly as they appear on the patient-provided report from the testing laboratory. GenomeConnect staff make no attempt to reinterpret the clinical significance of the variant.

Functional evidence

Functional consequence	Method	Result	Submitter	More information
sequence_variant_affecting_splicing (SO:1000071)			Lifecell International Pvt. Ltd Accession: SCV001482472.2 First in ClinVar: Mar 07, 2021 Last updated: Mar 07, 2021

Comment:

Citations for this variant

Title	Author	Journal	Year	Link
CYP21A2 mutations in pediatric patients with congenital adrenal hyperplasia in Costa Rica.	Umaña-Calderón A	Molecular genetics and metabolism reports	2021	PMID: 33604243
The spectrum of CYP21A2 gene mutations in patients with classic salt wasting form of 2l-hydroxylase deficiency in a Chinese cohort.	Liu Y	Molecular genetics & genomic medicine	2020	PMID: 32959514
Genetic characterization of a large cohort of Argentine 21-hydroxylase Deficiency.	Fernández CS	Clinical endocrinology	2020	PMID: 32289882
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
Identification of novel and rare CYP21A2 variants in Chinese patients with congenital adrenal hyperplasia due to 21-hydroxylase deficiency.	Xu J	Clinical biochemistry	2019	PMID: 30995443
Clinical characteristics of Taiwanese children with congenital adrenal hyperplasia due to 21-hydroxylase deficiency detected by neonatal screening.	Liu SY	Journal of the Formosan Medical Association = Taiwan yi zhi	2018	PMID: 28392195
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
A Case of Bilateral Testicular Tumors Subsequently Diagnosed as Congenital Adrenal Hyperplasia Due to 21-Hydroxylase Deficiency.	Sha YK	International journal of fertility & sterility	2016	PMID: 26985347
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
Standards and guidelines for the interpretation of sequence variants: a joint consensus recommendation of the American College of Medical Genetics and Genomics and the Association for Molecular Pathology.	Richards S	Genetics in medicine : official journal of the American College of Medical Genetics	2015	PMID: 25741868
A CYP21A2 gene mutation in patients with congenital adrenal hyperplasia. Molecular genetics report from Saudi Arabia.	Mohamed S	Saudi medical journal	2015	PMID: 25630015
High frequency of splice site mutation in 21-hydroxylase deficiency children.	Sharaf S	Journal of endocrinological investigation	2015	PMID: 25501839
Secondary amenorrhoea associated with high serum 17-hydroxyprogesterone levels revealing a heterozygous CYP21A2 mutation in a woman with Addison disease.	Boscolo M	Clinical endocrinology	2015	PMID: 25353971
The frequency and the effects of 21-hydroxylase gene defects in congenital adrenal hyperplasia patients.	Kirac D	Annals of human genetics	2014	PMID: 25227725
Genotype-phenotype correlation in 27 pediatric patients in congenital adrenal hyperplasia due to 21-hydroxylase deficiency in a single center.	Yoo Y	Annals of pediatric endocrinology & metabolism	2013	PMID: 24904866
A case with combined rare inborn metabolic disorders: congenital adrenal hyperplasia and ornithine transcarbamylase deficiency.	Kim YM	Gene	2013	PMID: 23769969
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
Phenotype-genotype correlations of 13 rare CYP21A2 mutations detected in 46 patients affected with 21-hydroxylase deficiency and in one carrier.	Tardy V	The Journal of clinical endocrinology and metabolism	2010	PMID: 20080860
Genetic analysis of two Japanese patients with non-classical 21-hydroxylase deficiency.	Imamine R	Internal medicine (Tokyo, Japan)	2009	PMID: 19420818
Inhibition of CYP21A2 enzyme activity caused by novel missense mutations identified in Brazilian and Scandinavian patients.	Soardi FC	The Journal of clinical endocrinology and metabolism	2008	PMID: 18381579
Ethnic-specific distribution of mutations in 716 patients with congenital adrenal hyperplasia owing to 21-hydroxylase deficiency.	Wilson RC	Molecular genetics and metabolism	2007	PMID: 17275379
CYP21 gene mutation analysis in 198 patients with 21-hydroxylase deficiency in The Netherlands: six novel mutations and a specific cluster of four mutations.	Stikkelbroeck NM	The Journal of clinical endocrinology and metabolism	2003	PMID: 12915679
Mutation of IVS2 -12A/C>G in combination with 707-714delGAGACTAC in the CYP21 gene is caused by deletion of the C4-CYP21 repeat module with steroid 21-hydroxylase deficiency.	Lee HH	The Journal of clinical endocrinology and metabolism	2003	PMID: 12788880
Three novel mutations in CYP21 gene in Brazilian patients with the classical form of 21-hydroxylase deficiency due to a founder effect.	Billerbeck AE	The Journal of clinical endocrinology and metabolism	2002	PMID: 12213891
Identification of non-amplifying CYP21 genes when using PCR-based diagnosis of 21-hydroxylase deficiency in congenital adrenal hyperplasia (CAH) affected pedigrees.	Day DJ	Human molecular genetics	1996	PMID: 8968761
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
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
Direct analysis of CYP21B genes in 21-hydroxylase deficiency using polymerase chain reaction amplification.	Owerbach D	Molecular endocrinology (Baltimore, Md.)	1990	PMID: 2325662
Aberrant splicing and missense mutations cause steroid 21-hydroxylase [P-450(C21)] deficiency in humans: possible gene conversion products.	Higashi Y	Proceedings of the National Academy of Sciences of the United States of America	1988	PMID: 2845408
A pilot newborn screening for congenital adrenal hyperplasia in Alaska.	Pang S	The Journal of clinical endocrinology and metabolism	1982	PMID: 7096533
An unusually high incidence of salt-losing congenital adrenal hyperplasia in the Alaskan Eskimo.	Hirschfeld AJ	The Journal of pediatrics	1969	PMID: 5804199
http://www.egl-eurofins.com/emvclass/emvclass.php?approved_symbol=CYP21A2	-	-	-	-
Miller, W. L. Personal Communication. 1996. San Francisco, Calif.	-	-	-	-

Text-mined citations for rs6467...

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Record last updated Oct 15, 2023

ClinVar Genomic variation as it relates to human health

NM_000500.9(CYP21A2):c.293-13C>G

NM_000500.9(CYP21A2):c.293-13C>G

Aggregate interpretations per condition

Clinical features observed in individuals with this variant

Submitted interpretations and evidence

Functional evidence

Citations for this variant

Text-mined citations for rs6467...