ClinVar Miner

Submissions for variant NM_000448.2(RAG1):c.2981A>G (p.His994Arg) (rs775412266)

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Total submissions: 2
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000412932 SCV000490764 likely pathogenic not provided 2016-05-18 criteria provided, single submitter clinical testing The H994Rvariant in the RAG1 gene has not been published as a pathogenic variant, nor has it been reported as a benignpolymorphism to our knowledge. The H994R variant was not observed in approximately 6,500 individualsof European and African American ancestry in the NHLBI Exome Sequencing Project, indicating it is nota common benign variant in these populations. The H994R variant is a conservative amino acidsubstitution, which occurs at a position that is well conserved across species. In silico analysis predicts thisvariant is probably damaging to the protein structure/function. Missense variants in a nearby residue(K992E and K992R) have been reported in the Human Gene Mutation Database in association withOmenn syndrome (Stenson et al., 2014), supporting the functional importance of this region of the protein.The H994R variant is a good candidate for a pathogenic variant, however the possibility it may be arare benign variant cannot be excluded.
Invitae RCV000687603 SCV000815180 uncertain significance Combined cellular and humoral immune defects with granulomas; Severe 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 arginine at codon 994 of the RAG1 protein (p.His994Arg). The histidine residue is highly conserved and there is a small physicochemical difference between histidine and arginine. This variant is present in population databases (rs775412266, ExAC 0.002%). This variant has been observed in combination with another rare missense variant in an individual affected with severe combined immunodeficiency (SCID) (Invitae). ClinVar contains an entry for this variant (Variation ID: 372489). 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: "Possibly 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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