ClinVar

Description

This sequence change replaces methionine, which is neutral and non-polar, with lysine, which is basic and polar, at codon 240 of the CYP21A2 protein (p.Met240Lys). 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. The c.719T>A (p.Met240Lys) variant alone has not been reported in the literature in individuals with CYP21A2-related conditions. However, it has been reported to co-occur with the c.710T>A (p.Ile237Asn) and c.713T>A (p.Val238Glu) variants in cis (on the same chromosome), which is known as the c.[710T>A;713T>A;719T>A] haplotype, E6 cluster, or CL6. This haplotype has been reported in the literature as homozygous or in combination with other CYP21A2 variants in individual(s) affected with classic salt-wasting, simple virilizing, and non-classic congenital adrenal hyperplasia due to 21-hydroxylase deficiency (PMID: 12915679, 1644925, 23359698, 26804566). This variant is also known as p.M239K. ClinVar contains an entry for this variant (Variation ID: 242688). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is not expected to disrupt CYP21A2 protein function. While the c.719T>A (p.Met240Lys) variant alone does not substantially affect CYP21A2 protein function, the c.[710T>A;713T>A;719T>A] haplotype has been reported to abolish enzyme activity (PMID: 15623806). In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance.