ClinVar Miner

Submissions for variant NM_000448.2(RAG1):c.1187G>A (p.Arg396His) (rs104894291)

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Total submissions: 2
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Invitae RCV000688686 SCV000816308 pathogenic Combined cellular and humoral immune defects with granulomas; Severe combined immunodeficiency, autosomal recessive, T cell-negative, B cell-negative, NK cell-positive 2019-12-11 criteria provided, single submitter clinical testing This sequence change replaces arginine with histidine at codon 396 of the RAG1 protein (p.Arg396His). The arginine residue is highly conserved and there is a small physicochemical difference between arginine and histidine. This variant is present in population databases (rs104894291, ExAC 0.006%). This variant has been reported in several individuals affected with Omenn syndrome, both in the compound heterozygous and homozygous states (PMID: 9630231, 17075247, 19830075). This variant is also known as G1299A in the literature. ClinVar contains an entry for this variant (Variation ID: 13146). Experimental studies have shown that this missense change, which is located in the nonamer binding domain, reduces binding of the RAG1 /RAG2 complex to the recombination signal sequence (RSS), decreases cleavage of the sequence junction, and impairs ability to mediate recombination of extrachromosomal substrates (PMID: 9630231, 21131235, 24290284). For these reasons, this variant has been classified as Pathogenic.
OMIM RCV000014028 SCV000034275 pathogenic Histiocytic medullary reticulosis 1998-05-29 no assertion criteria provided literature only

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