Submissions for variant NM_000500.9(CYP21A2):c.332_339del (p.Gly111fs)

dbSNP: rs387906510

Total submissions: 12

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Athena Diagnostics	RCV000711378	SCV000841741	pathogenic	not provided	2023-04-07	criteria provided, single submitter	clinical testing	This variant is expected to result in the loss of a functional protein. 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 multiple individuals, this variant has been seen in trans with other recessive pathogenic variants in CYP21A2, suggesting this variant is also pathogenic. In some published literature, this variant is referred to as c.329_336del, g.707_714del, p.Gly110fs, or as the 8 bp deletion in exon 3.
Myriad Genetics, Inc.	RCV000012946	SCV001194143	pathogenic	Classic congenital adrenal hyperplasia due to 21-hydroxylase deficiency	2019-12-17	criteria provided, single submitter	clinical testing	NM_000500.7(CYP21A2):c.332_339del8(G111Vfs*21) is classified as pathogenic in the context of congenital adrenal hyperplasia, CYP21A2-related and is associated with classic disease. Sources cited for classification include the following: PMID 25227725, 8081391, 23359698, 25121463 and 12788880 . Classification of NM_000500.7(CYP21A2):c.332_339del8(G111Vfs*21) is based on the following criteria: The variant causes a premature termination codon that is expected to be targeted by nonsense-mediated mRNA decay and is reported in individuals with the relevant phenotype. Please note: this variant was assessed in the context of healthy population screening.
Revvity Omics, Revvity	RCV000711378	SCV002018111	pathogenic	not provided	2023-09-13	criteria provided, single submitter	clinical testing
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV000711378	SCV002046176	pathogenic	not provided	2023-04-07	criteria provided, single submitter	clinical testing	The c.332_339del (p.Gly111Valfs*21) (also known as c.332_339del8 (G110del8nt)) variant alters the translational reading frame of the CYP21A2 mRNA and causes the premature termination of CYP21A2 protein synthesis. This pathogenic variant is associated with salt wasting CAH (PMIDs: 2827462 (1988), 23359698 (2013), and 25227725 (2014)). Based on the available information, this variant is classified as pathogenic.
Labcorp Genetics (formerly Invitae), Labcorp	RCV000711378	SCV002182512	pathogenic	not provided	2022-10-31	criteria provided, single submitter	clinical testing	This sequence change creates a premature translational stop signal (p.Gly111Valfs*21) in the CYP21A2 gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in CYP21A2 are known to be pathogenic (PMID: 10857554). 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 premature translational stop signal has been observed in individual(s) with classic salt-wasting, simple virilizing, and non-classic congenital adrenal hyperplasia due to 21-hydroxylase deficiency (PMID: 7749410, 8081391, 23359698, 25227725, 26804566). This variant is also known as 706del8, 707_714del8, E3del8bp, c.711_718delGAGACTAC. ClinVar contains an entry for this variant (Variation ID: 12164). For these reasons, this variant has been classified as Pathogenic.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000012946	SCV003845012	pathogenic	Classic congenital adrenal hyperplasia due to 21-hydroxylase deficiency	2023-02-20	criteria provided, single submitter	clinical testing	Variant summary: CYP21A2 c.332_339delGAGACTAC (p.Gly111ValfsX21) results in a premature termination codon, predicted to cause a truncation of the encoded protein or absence of the protein due to nonsense mediated decay, which are commonly known mechanisms for disease. Truncations downstream of this position have been classified as pathogenic by our laboratory. The variant was absent in 246380 control chromosomes (gnomAD). c.332_339delGAGACTAC has been reported in the literature in multiple compound heterozygous and homozygous individuals affected with Congenital Adrenal Hyperplasia (Wilson_2007, Milacic_2015). These data indicate that the variant is very likely to be associated with disease. Functional studies report experimental evidence evaluating an impact on protein function and results in null activity based on in vitro studies. Five ClinVar submitters (evaluation after 2014) cite this variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic.
Greenwood Genetic Center Diagnostic Laboratories, Greenwood Genetic Center	RCV000012946	SCV004013232	pathogenic	Classic congenital adrenal hyperplasia due to 21-hydroxylase deficiency	2023-05-19	criteria provided, single submitter	clinical testing	PVS1, PS3
Victorian Clinical Genetics Services, Murdoch Childrens Research Institute	RCV000012946	SCV005086882	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 hyperandrogenism nonclassic type due to 21-hydroxylase deficiency (MIM#201910). (I) 0106 - This gene is associated with autosomal recessive disease. (I) 0201 - Variant is predicted to cause nonsense-mediated decay (NMD) and loss of protein (premature termination codon is located at least 54 nucleotides upstream of the final exon-exon junction). (SP) 0251 - This variant is heterozygous (according to Fulgent Genetics report). (I) 0304 - Variant is present in gnomAD <0.01 for a recessive condition (v3: 16 heterozygotes, 0 homozygotes). However, please note this variant has failed a filter used for quality control in gnomAD v3. (SP) 0701 - Other variants predicted to result in NMD comparable to the one identified in this case have very strong previous evidence for pathogenicity (DECIPHER). (SP) 0801 - This variant has very strong previous evidence of pathogenicity in unrelated individuals. It has been detected in multiple compound heterozygous patients (ClinVar, PMIDs: 35079965, 26804566). (SP) 1208 - Inheritance information for this variant is not currently available in this individual. (I) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign
Juno Genomics, Hangzhou Juno Genomics, Inc	RCV000012946	SCV005416269	pathogenic	Classic congenital adrenal hyperplasia due to 21-hydroxylase deficiency		criteria provided, single submitter	clinical testing	PM2+PM3_VeryStrong+PVS1
Genomic Medicine Center of Excellence, King Faisal Specialist Hospital and Research Centre	RCV000012946	SCV005421024	pathogenic	Classic congenital adrenal hyperplasia due to 21-hydroxylase deficiency	2024-12-10	criteria provided, single submitter	clinical testing	PVS1, PM2, PP5
OMIM	RCV000012946	SCV000033190	pathogenic	Classic congenital adrenal hyperplasia due to 21-hydroxylase deficiency	2003-06-01	no assertion criteria provided	literature only
GeneReviews	RCV000012946	SCV000086798	pathologic	Classic congenital adrenal hyperplasia due to 21-hydroxylase deficiency	2013-08-29	no assertion criteria provided	curation	Converted during submission to Pathogenic.