ClinVar

Description

Variant summary: The variant identified by MLPA or other technology involves the deletion of exons 4-7 in the CYP21A2 gene. A presumed nomenclature of c.(447+1_448-1)_(939+1_940-1)del has been designated for the purposes of this classification. Although exact breakpoints of this CNV are not known, it is expected to result in a large in-frame deletion change in the CYP21A2 gene, a known mechanism of disease. Missense variants and in-frame deletions within this region have been reported as pathogenic by our lab and in ClinVar and are cited in association with Adrenal hyperplasia in HGMD. The frequency of this variant in the general population could not be determined as the technology used for structural variants in large population databases (gnomAD, Structural Variants database) could not detect variants of this type in CYP21A2. Additionally, allele frequency data in this gene may be confounded due to possible pseudogene overlap. Exon 4-7 deletion/conversions have been reported in the literature in individuals affected with Congenital Adrenal Hyperplasia (e.g., Xia_2022). To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. The following publications have been ascertained in the context of this evaluation (PMID: 10427156, 35882282). 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.