ClinVar Miner

Submissions for variant NM_000500.9(CYP21A2):c.1280G>A (p.Arg427His)

gnomAD frequency: 0.00001  dbSNP: rs151344504
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Total submissions: 3
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Labcorp Genetics (formerly Invitae), Labcorp RCV001851813 SCV002239464 pathogenic not provided 2021-11-19 criteria provided, single submitter clinical testing This sequence change replaces arginine, which is basic and polar, with histidine, which is basic and polar, at codon 427 of the CYP21A2 protein (p.Arg427His). 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. This missense change has been observed in individual(s) with classic salt-wasting and/or simple virilizing congenital adrenal hyperplasia due to 21-hydroxylase deficiency (PMID: 11600539, 30995443). It has also been observed to segregate with disease in related individuals. This variant is also known as R426H. ClinVar contains an entry for this variant (Variation ID: 12175). 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. Experimental studies have shown that this missense change affects CYP21A2 function (PMID: 11600539). This variant disrupts the p.Arg427 amino acid residue in CYP21A2. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 12213891, 18381579, 30995443). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. For these reasons, this variant has been classified as Pathogenic.
PreventionGenetics, part of Exact Sciences RCV003390673 SCV004118889 pathogenic CYP21A2-related disorder 2022-09-25 criteria provided, single submitter clinical testing The CYP21A2 c.1280G>A variant is predicted to result in the amino acid substitution p.Arg427His. This variant has been reported to be associated with classic congenital adrenal hyperplasia (CAH) due to significantly decreased enzyme activity (also known as R426H; reported in three sisters with simple virilizing CAH at Baumgartner-Parzer et al. 2001. PubMed ID: 11600539; reported in a salt-wasting CAH patient at Xu et al. 2019. PubMed ID: 30995443). This variant could be a naturally occurring variant in the CYP21A2 gene or a rare deleterious variant originated from the pseudogene CYP21A1P via gene conversion. This variant is interpreted as pathogenic.
OMIM RCV000012957 SCV000033201 pathogenic Classic congenital adrenal hyperplasia due to 21-hydroxylase deficiency 2001-10-01 no assertion criteria provided literature only

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