Total submissions: 7
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| Eurofins Ntd Llc |
RCV000173141 | SCV000224230 | benign | not specified | 2015-02-23 | criteria provided, single submitter | clinical testing | |
| Mendelics | RCV000012965 | SCV001137076 | benign | Classic congenital adrenal hyperplasia due to 21-hydroxylase deficiency | 2019-05-28 | criteria provided, single submitter | clinical testing | |
| Women's Health and Genetics/Laboratory Corporation of America, |
RCV002307363 | SCV002050902 | likely pathogenic | Congenital adrenal hyperplasia | 2022-10-01 | criteria provided, single submitter | clinical testing | Variant summary: CYP21A2 c.188A>T (p.His63Leu) results in a non-conservative amino acid change in the encoded protein sequence. Four of five in-silico tools predict a benign effect of the variant on protein function. The variant was present at a high frequency in 7520 out of 19,2468 control chromosomes in the gnomAD database, however, the inability of this data to distinguish the occurrence of this variant in the CYP21A1P pseudogene versus the real CYP21A2 gene makes this data unreliable to formulate conclusive opinions. In a cross-sectional review of the literature, c.188A>T has been reported in isolation as a compound heterozygote in trans with other CYP21A2 alleles in individuals affected with non-classic and simple virilizing forms of Congenital Adrenal Hyperplasia (example, Menassa_2008, Taboas_2013, Fernandez_2020, Nagasaki_2009) as well as a complex allele in cis with other putative CYP21A2 alleles (example, Soardi_2008, Liu_2022) and as a non-informative genotype (without a clear second allele specification) (example, Wang_2021, Yoon_2021). At-least one of these studies reports comprehensive genotyping utilizing orthogonal technologies to confirm the allele origin (example, Fernandez_2020). A recent report by the European Molecular Genetics Quality Network (EMQN) describing the best practice guidelines for molecular genetic testing and reporting of 21-hydroxylase deficiency lists this variant among those classified as "definitely pathogenic" for a non-classic phenotype (Baumgartner-Parzer_2020). These data indicate that the variant in isolation is likely to be associated with disease. At least two publications report experimental evidence evaluating an impact on protein function. The most pronounced variant effect results in variable levels of CYP21A2 enzyme activity depending upon the substrate utilized, namely 17-Hydroxyprogesterone or Progesterone. The reported activities range from one study reporting 70.8% of WT for conversion of 17OHP to 11-deoxycortisol (i.e., a 29.2% reduction in activity) and 66.5% of WT for conversion of Progesterone to 11-Deoxycorticosterone (DOC) (i.e., a 33.5% reduction in activity) with a similar reduction in maximal velocity (Vmax) (72.17% and 69.16% respectively) (Menassa_2008), while another study reporting a more pronounced impact on activity, 44.5% of WT with 17-OHP substrate and 20.7% of WT with Progesterone substrate (Soardi_2008) and a more pronounced impact of maximal velocity (Vmax) (13% and 8.65% respectively). Two clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All laboratories classified the variant as benign. Based on the evidence outlined above, the variant was classified as likely pathogenic. |
| Athena Diagnostics | RCV002472929 | SCV002771866 | pathogenic | not provided | 2022-09-28 | 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. In some published literature, this variant is referred to as c.185A>T (p.His62Leu). This variant has been seen in trans with other recessive pathogenic CYP21A2 variants in multiple individuals with congenital and also nonclassic forms of CAH. Assessment of experimental evidence suggests this variant results in abnormal protein function. See PMID: 18319307, 18381579. |
| Quest Diagnostics Nichols Institute San Juan Capistrano | RCV002472929 | SCV004221768 | pathogenic | not provided | 2022-09-28 | criteria provided, single submitter | clinical testing | The variant has been found in at least one symptomatic individual. Functional evidence suggests that this variant may impact protein function. The variant occurs in multiple cases with a lone recessive pathogenic/likely pathogenic variant in the same gene, and have phenotype known to be consistent with disease. Based on the available information, this variant is classified as pathogenic. |
| Breakthrough Genomics, |
RCV002472929 | SCV005225558 | likely benign | not provided | criteria provided, single submitter | not provided | ||
| OMIM | RCV000012965 | SCV000033209 | pathogenic | Classic congenital adrenal hyperplasia due to 21-hydroxylase deficiency | 2008-06-01 | no assertion criteria provided | literature only |