ClinVar Miner

Submissions for variant NM_000448.2(RAG1):c.1421G>A (p.Arg474His) (rs199474686)

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Total submissions: 2
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Invitae RCV000791763 SCV000931025 pathogenic Combined cellular and humoral immune defects with granulomas; Severe combined immunodeficiency, autosomal recessive, T cell-negative, B cell-negative, NK cell-positive 2019-12-31 criteria provided, single submitter clinical testing This sequence change replaces arginine with histidine at codon 474 of the RAG1 protein (p.Arg474His). The arginine residue is highly conserved and there is a small physicochemical difference between arginine and histidine. This variant is present in population databases (rs199474686, ExAC 0.02%). This variant has been reported as compound heterozygous in multiple individuals affected with Omenn Syndrome (PMID: 11133745, 18822103, 11313270). This variant is also known as 1533G>A in the literature. ClinVar contains an entry for this variant (Variation ID: 68684). Experimental studies have shown that this missense change significantly impaired VDJ recombinase activity of the protein (PMID: 11313270). This variant disrupts the p.Arg474 amino acid residue in RAG1. Other variant(s) that disrupt this residue have been observed in affected individuals (PMID: 19064334 and 16960852), suggesting that it is a clinically significant residue. As a result, variants that disrupt this residue are likely to be causative of disease. For these reasons, this variant has been classified as Pathogenic.
UniProtKB/Swiss-Prot RCV000059565 SCV000091097 not provided not provided no assertion provided not provided

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