ClinVar Miner

Submissions for variant NM_000448.2(RAG1):c.2095C>T (p.Arg699Trp) (rs199474676)

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Total submissions: 2
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Invitae RCV000548870 SCV000638114 likely pathogenic Severe combined immunodeficiency, autosomal recessive, T cell-negative, B cell-negative, NK cell-positive 2017-06-28 criteria provided, single submitter clinical testing This sequence change replaces arginine with tryptophan at codon 699 of the RAG1 protein (p.Arg699Trp). The arginine residue is highly conserved and there is a moderate physicochemical difference between arginine and tryptophan. This variant is present in population databases (rs199474676, ExAC 0.01%). This variant has been reported as homozygous or in combination with other RAG1 variants in individuals affected with RAG1-related diseases (PMID: 21771083, 24122031, 21184155, 20956421, 24290284).  This variant is also known as 2219C>T in the literature. ClinVar contains an entry for this variant (Variation ID: 68689). 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. A patient homozygous for this variant demonstrated low, but not absent, T and B cells and retained the ability to make functional antibodies, suggesting that this patient's lymphocytes had residual RAG activity and that the c.2095C>T variant only partially disrupts RAG function (PMID: 24122031). In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic.
UniProtKB/Swiss-Prot RCV000059570 SCV000091102 not provided not provided no assertion provided not provided

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