ClinVar Miner

Submissions for variant NM_000500.9(CYP21A2):c.719T>A (p.Met240Lys)

gnomAD frequency: 0.00523  dbSNP: rs6476
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Total submissions: 5
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
3billion RCV002250603 SCV002521530 likely benign Classic congenital adrenal hyperplasia due to 21-hydroxylase deficiency 2022-05-22 criteria provided, single submitter clinical testing The variant is observed as homozygous in at least two unrelated individuals/adults in the gnomAD v.2.1.1 dataset, being considered benign, however it is informative in the circumstances for the cluster of variants for pathogenicity. In silico tool predictions suggest no damaging effect of the variant on gene or gene product (REVEL: 0.18; 3Cnet: 0.04). Same nucleotide change resulting in same amino acid change has been previously reported to be associated with CYP21A2 related disorder (ClinVar ID: VCV000242688). Therefore, this variant is classified as pathogenic according to the recommendation of ACMG/AMP guideline.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV002298552 SCV002598641 likely benign not specified 2023-12-07 criteria provided, single submitter clinical testing Variant summary: CYP21A2 c.719T>A (p.Met240Lys) 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 0.001 in 250242 control chromosomes, predominantly at a frequency of 0.013 within the African or African-American subpopulation in the gnomAD database, including 1 homozygotes (14 total homozygotes in gnomAD V4). This observation needs to be cautiously considered due to the possibility of the CYP21A1P pseudogene being captured, although the observation of 14 homozygotes decreases the likelihood of a pseudogene artifact. p.M240K is found to be part of a recurrent cluster of 3 variants (I237N, V238E and M240K), which belongs to a group of common, pseudogene-derived mutations that are found in patients with classical CAH. This cluster of 3 variants is assumed to be transferred together from the CYP21A1P pseudogene to CYP21A2 in a continuous stretch of DNA (Robins_2005). To our knowledge, p.M240K has been reported in the literature as part of this cluster of 3 variants in individuals affected with Congenital Adrenal Hyperplasia (e.g. Higashi_1991, Barbat_1995, Chang_2011, Kirac_2014, Essawi_2020, Wang_2021, Turan_2022). These reports do not provide unequivocal conclusions about association of the p.M240K variant alone with Congenital Adrenal Hyperplasia. Experimental evidence evaluating an impact on protein function demonstrated that the p.M240K variant alone had no effect on enzyme activity and consequently does not contribute to the disease (Robins_2005). The following publications have been ascertained in the context of this evaluation (PMID: 7749410, 32616876, 21117955, 32614782, 1869518, 25227725, 15623806, 2249999, 33864926, 31586465). Three submitters have cited clinical-significance assessments for this variant to ClinVar after 2014. One submitter classified the variant as pathogenic, one submitter classified the variant as VUS and one submitter classified the variant as likely benign. Based on the evidence outlined above, the variant was classified as likely benign.
Labcorp Genetics (formerly Invitae), Labcorp RCV001269964 SCV003256720 uncertain significance not provided 2022-10-31 criteria provided, single submitter clinical testing 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.
Center for Genomic Medicine, King Faisal Specialist Hospital and Research Center RCV002250603 SCV005421028 uncertain significance Classic congenital adrenal hyperplasia due to 21-hydroxylase deficiency 2024-12-10 criteria provided, single submitter clinical testing PM1, PP2, BP4
Clinical Genetics and Genomics, Karolinska University Hospital RCV001269964 SCV001450354 pathogenic not provided 2017-05-23 flagged submission clinical testing

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