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

dbSNP: rs6467

Total submissions: 34

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Eurofins Ntd Llc (ga)	RCV000711376	SCV000330929	pathogenic	not provided	2015-07-24	criteria provided, single submitter	clinical testing
Institute of Human Genetics Munich, Klinikum Rechts Der Isar, TU München	RCV000012939	SCV000680184	pathogenic	Classic congenital adrenal hyperplasia due to 21-hydroxylase deficiency	2017-10-26	criteria provided, single submitter	clinical testing
Ambry Genetics	RCV000624227	SCV000741505	pathogenic	Inborn genetic diseases	2016-04-22	criteria provided, single submitter	clinical testing
Athena Diagnostics	RCV000711376	SCV000841739	pathogenic	not provided	2023-03-28	criteria provided, single submitter	clinical testing	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).
Fulgent Genetics, Fulgent Genetics	RCV000012939	SCV000893711	pathogenic	Classic congenital adrenal hyperplasia due to 21-hydroxylase deficiency	2018-10-31	criteria provided, single submitter	clinical testing
Mendelics	RCV000012939	SCV001137077	pathogenic	Classic congenital adrenal hyperplasia due to 21-hydroxylase deficiency	2019-05-28	criteria provided, single submitter	clinical testing
Myriad Genetics, Inc.	RCV000012939	SCV001194142	pathogenic	Classic congenital adrenal hyperplasia due to 21-hydroxylase deficiency	2019-12-20	criteria provided, single submitter	clinical testing	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.
New York Genome Center	RCV001263256	SCV001441293	pathogenic	Adrenal hyperplasia	2020-01-08	criteria provided, single submitter	clinical testing
Illumina Laboratory Services, Illumina	RCV000012939	SCV001451452	pathogenic	Classic congenital adrenal hyperplasia due to 21-hydroxylase deficiency	2019-01-15	criteria provided, single submitter	clinical testing	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.
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV000711376	SCV001469963	pathogenic	not provided	2023-03-28	criteria provided, single submitter	clinical testing	The CYP21A2 c.293-13C>G variant (also known as IVS2-13A/C>G or Intron 2G) has been reported in the published literature to disrupt normal splicing of the CYP21A2 mRNA (PMID: 2845408 (1988)) and is usually associated with classic CAH, either simple virilizing or salt wasting (PMIDs: 1644925 (1992), 12213891 (2002), 12788880 (2003), 12915679 (2003), 18381579 (2008), 31586465 (2020), 32289882 (2020), 32959514 (2020)). The frequency of this variant in the general population, 0.0037 (36/9714 chromosomes (Genome Aggregation Database, http://gnomad.broadinstitute.org)), is consistent with pathogenicity. Based on the available information, this variant is classified as pathogenic.
Baylor Genetics	RCV000012939	SCV001524846	pathogenic	Classic congenital adrenal hyperplasia due to 21-hydroxylase deficiency	2023-05-03	criteria provided, single submitter	clinical testing
Genomics England Pilot Project, Genomics England	RCV000012939	SCV001760175	likely pathogenic	Classic congenital adrenal hyperplasia due to 21-hydroxylase deficiency		criteria provided, single submitter	clinical testing
Institute of Human Genetics, University of Leipzig Medical Center	RCV000012939	SCV001950083	pathogenic	Classic congenital adrenal hyperplasia due to 21-hydroxylase deficiency	2021-07-21	criteria provided, single submitter	clinical testing	This variant was identified as compound heterozygous with NM_000500.9:c.?_939+50del.
Revvity Omics, Revvity	RCV000711376	SCV002018113	pathogenic	not provided	2023-03-20	criteria provided, single submitter	clinical testing
Greenwood Genetic Center Diagnostic Laboratories, Greenwood Genetic Center	RCV000711376	SCV002051558	pathogenic	not provided	2021-02-05	criteria provided, single submitter	clinical testing	PS3, PS4
Labcorp Genetics (formerly Invitae), Labcorp	RCV000711376	SCV002243459	pathogenic	not provided	2024-01-26	criteria provided, single submitter	clinical testing	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.
Provincial Medical Genetics Program of British Columbia, University of British Columbia	RCV000012939	SCV002320847	pathogenic	Classic congenital adrenal hyperplasia due to 21-hydroxylase deficiency	2023-12-28	criteria provided, single submitter	clinical testing
Institute of Human Genetics, University Hospital Muenster	RCV004584324	SCV002506419	pathogenic	See cases	2018-10-19	criteria provided, single submitter	clinical testing	ACMG categories: PS3,PM2,PM3,PP1,PP4,PP5
3billion	RCV000012939	SCV002521128	pathogenic	Classic congenital adrenal hyperplasia due to 21-hydroxylase deficiency	2022-05-22	criteria provided, single submitter	clinical testing	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.
Al Jalila Children’s Genomics Center, Al Jalila Childrens Speciality Hospital	RCV000711376	SCV002818261	pathogenic	not provided	2022-12-17	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000012939	SCV003922698	pathogenic	Classic congenital adrenal hyperplasia due to 21-hydroxylase deficiency	2023-03-15	criteria provided, single submitter	clinical testing	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.
Center for Genomic Medicine, King Faisal Specialist Hospital and Research Center	RCV000012939	SCV004809970	likely pathogenic	Classic congenital adrenal hyperplasia due to 21-hydroxylase deficiency	2024-04-04	criteria provided, single submitter	clinical testing
Human Genome Sequencing Center Clinical Lab, Baylor College of Medicine	RCV004556714	SCV005045740	pathogenic	Congenital adrenal hyperplasia	2020-06-18	criteria provided, single submitter	clinical testing	This c.293-13C>G variant is among the most frequent pathogenic variants in patients with classic congenital adrenal hyperplasia due to 21-hydroxylase deficiency [OMIM 613815.0006]. It causes premature splicing of the intron and a shift in the translational reading frame [PMID 15146390, 25525159]. This variant has been detected in 206 heterozygous and 2 homozygous individuals from the ExAC population database (http://exac.broadinstitute.org/variant/16-3293310-A-G) and in affected patients at the homozygous state in our internal database. This variant is classified as pathogenic. Homozygosity for this variant is also considered medically actionable.
Laboratory of Medical Genetics, National & Kapodistrian University of Athens	RCV000012939	SCV005051736	pathogenic	Classic congenital adrenal hyperplasia due to 21-hydroxylase deficiency	2024-02-01	criteria provided, single submitter	curation
Victorian Clinical Genetics Services, Murdoch Childrens Research Institute	RCV000012939	SCV005086881	pathogenic	Classic congenital adrenal hyperplasia due to 21-hydroxylase deficiency	2023-07-16	criteria provided, single submitter	clinical testing	Based on the classification scheme VCGS_Germline_v1.3.4, this variant is classified as Pathogenic. Following criteria are met: 0102 - Loss of function is a known mechanism of disease in this gene and is associated with congenital adrenal hyperplasia, due to 21-hydroxylase deficiency (MIM#201910) and nonclassic type hyperandrogenism, due to 21-hydroxylase deficiency (MIM#201910). (I) 0106 - This gene is associated with autosomal recessive disease. (I) 0210 - Splice site variant proven to affect splicing of the transcript with a known effect on protein sequence. RNA studies have shown that this variant causes aberrant splicing which is predicted to cause a frameshift and create a premature termination codon (PMID: 2845408). (SP) 0252 - This variant is homozygous. (I) 0304 - Variant is present in gnomAD (v3) <0.01 for a recessive condition (325 heterozygotes, 1 homozygote). (SP) 0508 - In silico predictions for abnormal splicing are conflicting. (I) 0801 - This variant has strong previous evidence of pathogenicity in unrelated individuals. This has been classified as pathogenic by mulitple clinical laboratories in ClinVar and is very well reported in both compound heterozygous and homozygous states in individuals with congenital adrenal hypoplasia (PMIDs: 35355919, 31586465, 32289882). (SP) 1209 - This variant has been shown to be both maternally and paternally inherited (biallelic) (by trio analysis). (I) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign
Breakthrough Genomics, Breakthrough Genomics	RCV000012939	SCV005088858	pathogenic	Classic congenital adrenal hyperplasia due to 21-hydroxylase deficiency	2020-10-27	criteria provided, single submitter	clinical testing	This variant is a well-established pathogenic variant and reported as the most frequent nondeletional mutation found in patients with classic congenital adrenal hyperplasia due to 21-hydroxylase deficiency [PMID: 20301350, 1644925, 2845408, 25041270]. The variant has been reported to cause aberrant splicing of intron 2 resulting in a shift in the translational reading frame [PMID: 20301350, 2845408, 1869518].
Clinical Genetics Laboratory, Skane University Hospital Lund	RCV000711376	SCV005197682	pathogenic	not provided	2022-08-18	criteria provided, single submitter	clinical testing
OMIM	RCV000012939	SCV000033181	pathogenic	Classic congenital adrenal hyperplasia due to 21-hydroxylase deficiency	2003-08-01	no assertion criteria provided	literature only
GeneReviews	RCV000012939	SCV000086795	pathologic	Classic congenital adrenal hyperplasia due to 21-hydroxylase deficiency	2013-08-29	no assertion criteria provided	curation	Converted during submission to Pathogenic.
GeneReviews	RCV000012939	SCV000086796	pathologic	Classic congenital adrenal hyperplasia due to 21-hydroxylase deficiency	2013-08-29	no assertion criteria provided	curation	Converted during submission to Pathogenic.
Lifecell International Pvt. Ltd	RCV000012939	SCV001482472	pathogenic	Classic congenital adrenal hyperplasia due to 21-hydroxylase deficiency		no assertion criteria provided	clinical testing	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).
GenomeConnect, ClinGen	RCV000012939	SCV002074917	not provided	Classic congenital adrenal hyperplasia due to 21-hydroxylase deficiency		no assertion provided	phenotyping only	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.
Zotz-Klimas Genetics Lab, MVZ Zotz Klimas	RCV000012939	SCV004171700	pathogenic	Classic congenital adrenal hyperplasia due to 21-hydroxylase deficiency	2023-11-24	no assertion criteria provided	clinical testing
Medical Laboratory Center, Huzhou Maternal and Child Health Hospital	RCV000012939	SCV004800923	pathogenic	Classic congenital adrenal hyperplasia due to 21-hydroxylase deficiency		no assertion criteria provided	research