Submissions for variant NM_000500.9(CYP21A2):c.713T>A (p.Val238Glu)

gnomAD frequency: 0.00001  dbSNP: rs12530380

Total submissions: 5

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Clinical Genetics and Genomics, Karolinska University Hospital	RCV001269963	SCV001450353	pathogenic	not provided	2017-05-23	criteria provided, single submitter	clinical testing
3billion	RCV002250459	SCV002521294	uncertain significance	Classic congenital adrenal hyperplasia due to 21-hydroxylase deficiency	2022-05-22	criteria provided, single submitter	clinical testing	The variant is observed at an extremely low frequency in the gnomAD v2.1.1 dataset (total allele frequency: <0.001%). Same nucleotide change resulting in same amino acid change has been previously reported to be associated with CYP21A2 related disorder (ClinVar ID: VCV000012173 / PMID: 26278268). 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	RCV002298442	SCV002598642	likely pathogenic	Congenital adrenal hyperplasia	2023-12-08	criteria provided, single submitter	clinical testing	Variant summary: CYP21A2 c.713T>A (p.Val238Glu) results in a non-conservative amino acid change in the encoded protein sequence. Three of five in-silico tools predict a damaging effect of the variant on protein function. The frequency data for this variant in gnomAD is considered unreliable, as metrics indicate poor data quality at this position. p.V238E 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), and has been reported in the literature in multiple individuals affected with Congenital Adrenal Hyperplasia (e.g. Higashi_1991, Barbat_1995, Chang_2011, Kirac_2014, Essawi_2020, Wang_2021, Liu_2023, Faradz_2023 ). Nevertheless, p.V238E has also been reported in the literature to occur on its own in individuals affected with Congenital Adrenal Hyperplasia (e.g. Kirac_2014, Forouzanfar_2015, Fernandez_2020). These data indicate that the variant is likely to be associated with disease. Furthermore, experimental evidence evaluating an impact on protein function demonstrated that the p.V238E variant alone abolishes enzyme function and is thus a null mutation (Robins_2005). The following publications have been ascertained in the context of this evaluation (PMID: 7749410, 32616876, 21117955, 32614782, 32289882, 26278268, 1869518, 25227725, 16430727, 15623806, 2249999, 33864926, 37699373, 36726778). Four submitters have cited clinical-significance assessments for this variant to ClinVar after 2014 and classified the variant as pathogenic (n=2) and VUS (n=2). Based on the evidence outlined above, the variant was classified as likely pathogenic.
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV001269963	SCV002774803	pathogenic	not provided	2021-03-28	criteria provided, single submitter	clinical testing
Labcorp Genetics (formerly Invitae), Labcorp	RCV001269963	SCV003439339	uncertain significance	not provided	2022-10-31	criteria provided, single submitter	clinical testing	This sequence change replaces valine, which is neutral and non-polar, with glutamic acid, which is acidic and polar, at codon 238 of the CYP21A2 protein (p.Val238Glu). 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.713T>A (p.Val238Glu) variant alone has been observed in an individual with classic salt-wasting congenital adrenal hyperplasia due to 21-hydroxylase deficiency (PMID: 26278268). It also frequently co-occurs with the c.710T>A (p.Ile237Asn) and c.719T>A (p.Met240Lys) 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.V237E. ClinVar contains an entry for this variant (Variation ID: 12173). 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 expected to disrupt CYP21A2 protein function. The c.713T>A (p.Val238Glu) variant alone affects CYP21A2 protein function, and 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.