ClinVar Miner

Submissions for variant NM_000475.5(NR0B1):c.1142T>C (p.Leu381Pro) (rs104894899)

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Total submissions: 2
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Invitae RCV000635250 SCV000756636 uncertain significance Congenital adrenal hypoplasia, X-linked; 46,XY sex reversal, type 2 2018-01-31 criteria provided, single submitter clinical testing This sequence change replaces leucine with proline at codon 381 of the NR0B1 protein (p.Leu381Pro). The leucine residue is highly conserved and there is a moderate physicochemical difference between leucine and proline. This variant is not present in population databases (ExAC no frequency). This variant has not been reported in the literature in individuals with NR0B1-related disease. Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be disruptive, but these predictions have not been confirmed by published functional studies and their clinical significance is uncertain. Different missense substitutions at this codon (p.L381H and p.L381F) have been determined in unrelated case reports (PMID: 11113848, 28546232). This suggests that the leucine residue may be critical for NR0B1 protein function. 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.
Clinical Molecular Genetics Laboratory,Johns Hopkins All Children's Hospital RCV000584385 SCV000692289 pathogenic Congenital adrenal hypoplasia, X-linked 2008-02-13 no assertion criteria provided clinical testing

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