ClinVar Miner

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

dbSNP: rs267606756
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Total submissions: 10
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Athena Diagnostics Inc 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 Omics 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
Invitae 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.
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.

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