Total submissions: 1
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| Illumina Laboratory Services, |
RCV000778524 | SCV000914806 | likely pathogenic | Glucocorticoid deficiency 1 | 2018-09-19 | criteria provided, single submitter | clinical testing | The MC2R c.437G>A (p.Arg146His) variant is described in three studies, found in a homozygous state in two individuals with glucocorticoid deficiency from two unrelated families in which the variant segregated with disease, in a compound heterozygous state with another missense variant in a two-year old girl with glucocorticoid deficiency, and in a compound heterozygous state with a frameshift variant in two siblings with an initial diagnosis of adrenal hypoplasia (Weber et al. 1995; Matsuura et al. 2006; Lin et al. 2007). Functional studies demonstrated that the p.Arg146His variant protein shows a significant reduction in cell surface expression and intracellular retention in the endoplasmic reticulum compared to wild type and is considered to be a trafficking-defect variant (Chung et al. 2008). The variant also resulted in a significant loss of maximal ACTH-stimulated activity and a loss of high-affinity binding to ACTH (Elias et al. 1999). The Arg146 residue is conserved. The highest reported frequency for this variant is 0.000242 from the South Asian population of the Exome Aggregation Consortium. Based on the available evidence, the p.Arg146His variant is classified as likely pathogenic for glucocorticoid deficiency. This variant was observed by ICSL as part of a predisposition screen in an ostensibly healthy population. |