ClinVar Miner

Submissions for variant NM_000448.2(RAG1):c.1232T>C (p.Leu411Pro) (rs1554944877)

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Total submissions: 1
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Invitae RCV000526312 SCV000646365 uncertain significance Combined cellular and humoral immune defects with granulomas; Severe combined immunodeficiency, autosomal recessive, T cell-negative, B cell-negative, NK cell-positive 2017-11-06 criteria provided, single submitter clinical testing This sequence change replaces leucine with proline at codon 411 of the RAG1 protein (p.Leu411Pro). 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 been reported as homozygous in an individual with severe combined immunodeficiency (SCID) (PMID: 24290284) and as a heterozygous variant in an individual with RAG1 reversion mosaicism and Omenn syndrome (PMID: 24817258). Experimental studies have shown that this missense change demonstrates disrupted recombination activity (PMID: 24290284, 24817258). In summary, this variant has a deleterious impact on RAG1 function in vitro and has been reported in affected individuals. However, additional genetic and/or functional data are needed to determine its role in disease. Therefore, it has been classified as a Variant of Uncertain Significance.

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