Submissions for variant NM_000500.9(CYP21A2):c.923dup (p.Leu308fs)

dbSNP: rs267606756

Total submissions: 12

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Athena Diagnostics	RCV000711389	SCV000841752	pathogenic	not provided	2023-04-13	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 with congenital adrenal hyperplasia, this variant has been seen in trans with other recessive pathogenic variants in CYP21A2.
Clinical Genetics and Genomics, Karolinska University Hospital	RCV000711389	SCV001450355	pathogenic	not provided	2017-05-23	criteria provided, single submitter	clinical testing
Revvity Omics, Revvity	RCV000711389	SCV002018110	pathogenic	not provided	2022-06-23	criteria provided, single submitter	clinical testing
DASA	RCV000055821	SCV002107077	pathogenic	Classic congenital adrenal hyperplasia due to 21-hydroxylase deficiency	2022-03-05	criteria provided, single submitter	clinical testing	The c.923dupT;p.((Leu308Phefs*6) is a null frameshift variant (NMD) in the CYP21A2 gene and predicts alteration of the nonsense-mediate decay - NMD is present in a relevant exon to the transcript - PVS1. This sequence change has been observed in affected individual(s) and ClinVar contains an entry for this variant (ClinVar ID: 65611; PMID: 20301350; PMID: 26206692; PMID: 29035424; PMID: 19169499) - PS4. The p.(Leu308Phefs*6) was detected in trans with a pathogenic variant (PMID: 29035424) - PM3. In summary, the currently available evidence indicates that the variant is pathogenic.
3billion	RCV000055821	SCV002521718	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: 0.006%). 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. Frameshift: predicted to result in a loss or disruption of normal protein function through nonsense-mediated decay (NMD) or protein truncation. Multiple pathogenic variants are reported downstream of the variant. The variant has been reported at least twice as pathogenic with clinical assertions and evidence for the classification (ClinVar ID: VCV000065611 / PMID: 1644925). Therefore, this variant is classified as pathogenic according to the recommendation of ACMG/AMP guideline.
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV000711389	SCV002774383	pathogenic	not provided	2023-04-13	criteria provided, single submitter	clinical testing	The c.923dup pathogenic variant (also known as F306+1nt, F306+ T, and L307 frameshift) alters the translation reading frame of the CYP21A2 mRNA and causes the premature termination (p.Leu308Phefs*6) of CYP21A2 protein synthesis. This pathogenic variant is associated with salt-wasting CAH. Based on the available information, this variant is classified as pathogenic.
Fulgent Genetics, Fulgent Genetics	RCV000055821	SCV002804022	pathogenic	Classic congenital adrenal hyperplasia due to 21-hydroxylase deficiency	2021-11-03	criteria provided, single submitter	clinical testing
Labcorp Genetics (formerly Invitae), Labcorp	RCV000711389	SCV003439325	pathogenic	not provided	2022-10-31	criteria provided, single submitter	clinical testing	This sequence change creates a premature translational stop signal (p.Leu308Phefs*6) 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 and simple virilizing congenital adrenal hyperplasia due to 21-hydroxylase deficiency (PMID: 1644925, 26804566, 28392195, 30995443, 31446012). This variant is also known as F306+T. ClinVar contains an entry for this variant (Variation ID: 65611). For these reasons, this variant has been classified as Pathogenic.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000055821	SCV003845011	pathogenic	Classic congenital adrenal hyperplasia due to 21-hydroxylase deficiency	2023-02-20	criteria provided, single submitter	clinical testing	Variant summary: CYP21A2 c.923dupT (p.Leu308PhefsX6) 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 246362 control chromosomes. c.923dupT has been reported in the literature in multiple individuals affected with Congenital Adrenal Hyperplasia (de Carvalho_2016, Ezquieta_1995, Friaes_2006, Higashi_1991, Luczay_2006, Speiser_1992), and some of these individuals are reported with other (likely) pathogenic variants in trans. 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 enzymatic activity, finding reduced activity when combined with a missense variant as compared to the missense variant alone or the wildtype construct (Khajuria_2018). Eight submitters have provided clinical-significance assessments for this variant to ClinVar after 2014, and all laboratories classified the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic.
Victorian Clinical Genetics Services, Murdoch Childrens Research Institute	RCV000055821	SCV005086883	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: 2 heterozygotes, 0 homozygotes). (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 including as part of complex alleles harbouring multiple variants (ClinVar, LOVD, 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
GeneReviews	RCV000055821	SCV000086804	pathologic	Classic congenital adrenal hyperplasia due to 21-hydroxylase deficiency	2013-08-29	no assertion criteria provided	curation	Converted during submission to Pathogenic.
Center for Genomic Medicine, King Faisal Specialist Hospital and Research Center	RCV000055821	SCV004807436	uncertain significance	Classic congenital adrenal hyperplasia due to 21-hydroxylase deficiency	2024-03-26	flagged submission	clinical testing