ClinVar Miner

Submissions for variant NM_000448.2(RAG1):c.2258A>T (p.His753Leu) (rs199474687)

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Total submissions: 2
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Invitae RCV000687602 SCV000815179 uncertain significance Combined cellular and humoral immune defects with granulomas; Severe combined immunodeficiency, autosomal recessive, T cell-negative, B cell-negative, NK cell-positive 2018-06-06 criteria provided, single submitter clinical testing This sequence change replaces histidine with leucine at codon 753 of the RAG1 protein (p.His753Leu). The histidine residue is highly conserved and there is a moderate physicochemical difference between histidine and leucine. This variant is present in population databases (rs199474687, ExAC 0.001%). This variant has been observed in combination with other rare missense variants in individuals affected with Omenn syndrome or severe combined immunodeficiency (SCID) (PMID: 11133745, Invitae). This variant is also known as A2370T in the literature. ClinVar contains an entry for this variant (Variation ID: 68690). 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. Additionally, an experimental study has shown that disruption of the corresponding amino acid in mice (His750) in combination with the disruption of amino acid Arg748, results in defective V(D)J recombination (PMID: 11971977). However, the effect of disrupting each amino acid alone was not assessed, therefore the clinical significance of this finding is unclear at this time. The observation of another missense substitution at this codon (p.His753Arg) in an  individual affected with SCID suggests that this may be a clinically significant residue (PMID: 24144642). 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.
UniProtKB/Swiss-Prot RCV000059571 SCV000091103 not provided not provided no assertion provided not provided

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