ClinVar Miner

Submissions for variant NM_000448.2(RAG1):c.335G>A (p.Arg112His) (rs749223640)

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Total submissions: 2
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000489989 SCV000577724 likely pathogenic not provided 2015-06-15 criteria provided, single submitter clinical testing The R112H variant in the RAG1 gene has not been published as a pathogenic variant, nor has it been reported as a benign polymorphism to our knowledge. The R112H variant was not observed in approximately 6,500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, indicating it is not a common benign variant in these populations. The R112H variant is a conservative amino acid substitution, which is not likely to impact secondary protein structure as these residues share similar properties. However, this substitution occurs at a position that is conserved across species, and in silico analysis predicts this variant is probably damaging to the protein structure/function. We interpret R112H as a strong candidate for a disease-causing variant, however the possibility it may be a rare benign variant cannot be excluded.
Invitae RCV000645684 SCV000767435 uncertain significance Combined cellular and humoral immune defects with granulomas; Severe immunodeficiency, autosomal recessive, T-cell negative, B-cell negative, NK cell-positive 2017-08-18 criteria provided, single submitter clinical testing This sequence change replaces arginine with histidine at codon 112 of the RAG1 protein (p.Arg112His). The arginine residue is highly conserved and there is a small physicochemical difference between arginine and histidine. This variant is present in population databases (rs749223640, ExAC 0.01%). This variant has not been reported in the literature in individuals with RAG1-related disease. ClinVar contains an entry for this variant (Variation ID: 427093). Algorithms developed to predict the effect of missense changes on protein structure and function do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Probably Damaging"; Align-GVGD: "Class C0"). 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.

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