ClinVar Miner

Submissions for variant NM_000448.3(RAG1):c.2981A>G (p.His994Arg)

gnomAD frequency: 0.00001  dbSNP: rs775412266
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Total submissions: 3
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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.
Labcorp Genetics (formerly Invitae), Labcorp RCV000687603 SCV000815180 pathogenic Combined immunodeficiency with skin granulomas; Severe combined immunodeficiency, autosomal recessive, T cell-negative, B cell-negative, NK cell-positive 2023-06-20 criteria provided, single submitter clinical testing For these reasons, this variant has been classified as Pathogenic. Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is expected to disrupt RAG1 protein function. ClinVar contains an entry for this variant (Variation ID: 372489). This missense change has been observed in individual(s) with clinical features of RAG1-related conditions (PMID: 33193364; Invitae). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. This variant is present in population databases (rs775412266, gnomAD 0.002%). This sequence change replaces histidine, which is basic and polar, with arginine, which is basic and polar, at codon 994 of the RAG1 protein (p.His994Arg).
Fulgent Genetics, Fulgent Genetics RCV005044627 SCV005683496 likely pathogenic Combined immunodeficiency due to partial RAG1 deficiency; Combined immunodeficiency with skin granulomas; Histiocytic medullary reticulosis; Severe combined immunodeficiency, autosomal recessive, T cell-negative, B cell-negative, NK cell-positive 2024-02-08 criteria provided, single submitter clinical testing

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