ClinVar Miner

Submissions for variant NM_000500.9(CYP21A2):c.1099C>T (p.Arg367Cys)

gnomAD frequency: 0.00016  dbSNP: rs758658540
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Total submissions: 2
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Institute of Medical Genetics and Genomics, Sir Ganga Ram Hospital RCV002211049 SCV002496420 uncertain significance Classic congenital adrenal hyperplasia due to 21-hydroxylase deficiency 2021-03-10 criteria provided, single submitter clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV002222762 SCV002500499 likely pathogenic Congenital adrenal hyperplasia 2022-03-02 criteria provided, single submitter clinical testing Variant summary: CYP21A2 c.1099C>T (p.Arg367Cys) results in a non-conservative amino acid change in the encoded protein sequence. Three of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 0.00026 in 248740 control chromosomes in the gnomAD database, including 1 homozygote. This frequency is not significantly higher than expected for a pathogenic variant in CYP21A2 causing Congenital Adrenal Hyperplasia (0.00026 vs 0.002), allowing no conclusion about variant significance. c.1099C>T has been reported in the literature as a compound heterozygous genotype in individuals affected with non-classical congenital adrenal hyperplasia (CAH) and supported by EMQN best practice guidelines for reporting 21-hydroxylase deficiency (example, Barbaro_2015, Khttab_2016, Baumgartner-Parzer_2020). These data indicate that the variant is likely to be associated with disease. At least one publication reports experimental evidence evaluating an impact on protein function (example, Barbaro_2015). The most pronounced variant effect results in 13% of normal activity (reflected by Vmax, as the kinetic constant) in vitro using progesterone as the natural substrate. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014. Based on the evidence outlined above, the variant was classified as likely pathogenic.

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