Total submissions: 3
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| Mendelics | RCV000987669 | SCV001137079 | uncertain significance | 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, |
RCV003155333 | SCV003844769 | likely benign | not specified | 2023-02-15 | criteria provided, single submitter | clinical testing | Variant summary: CYP21A2 c.797C>T (p.Ala266Val) 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 allele was found at a frequency of 0.0019 in 247160 control chromosomes, predominantly at a frequency of 0.0049 within the Latino subpopulation in the gnomAD database. The observed variant frequency within Latino control individuals in the gnomAD database is approximately 2.4 fold of the estimated maximal expected allele frequency for a pathogenic variant in CYP21A2 causing Congenital Adrenal Hyperplasia phenotype (0.002). This data must be used with caution as a highly homologous pseudogene has not been ruled out as the source of the variant alleles in gnomad. c.797C>T has been reported in the literature in heterozygous individuals affected with Congenital Adrenal Hyperplasia without evidence of cosegregation (Bleiken_2008, Marques_2010, Malikova_2012, Coeli-Lacchini_2013), and with some reported with missense variants of unknown significance in cis or in trans. These reports do not provide unequivocal conclusions about association of the variant with Congenital Adrenal Hyperplasia. In some patients, co-occurrence with another truncating pathogenic variant was reported in cis (CYP21A2 c.955C>T, p.Gln319Ter), providing supporting evidence for a benign role. At least one publication reports experimental evidence evaluating an impact on protein function, showing similar enzymatic activity as the wildtype protein in a yeast co-expression system (Bleicken_2008). One submitter has provided a clinical-significance assessment for this variant to ClinVar after 2014 without evidence for independent evaluation, and classified the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as likely benign. |
| Quest Diagnostics Nichols Institute San Juan Capistrano | RCV004997549 | SCV005625737 | uncertain significance | not provided | 2024-01-08 | criteria provided, single submitter | clinical testing |