ClinVar Miner

Submissions for variant NM_000448.3(RAG1):c.549G>A (p.Met183Ile)

gnomAD frequency: 0.00001  dbSNP: rs750394886
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Total submissions: 2
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Center for Genomics, Ann and Robert H. Lurie Children's Hospital of Chicago RCV000768064 SCV000898926 uncertain significance 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 2021-03-30 criteria provided, single submitter clinical testing RAG1 NM_000448.2 exon 2 p.Met183Ile (c.549G>A): This variant has not been reported in the literature but is present in 0.03% (12/33574) of Latino alleles in the Genome Aggregation Database (http://gnomad.broadinstitute.org/variant/11-36595403-G-A). This variant amino acid Isoleucine (Ile) is present in >20 species and is not well conserved among evolutionarily distant species; this suggests that this variant may not impact the protein. Additional computational prediction tools do not suggest an impact. In summary, data on this variant is insufficient for disease classification. Therefore, the clinical significance of this variant is uncertain.
Invitae RCV002536598 SCV003466288 uncertain significance Combined immunodeficiency with skin granulomas; Severe combined immunodeficiency, autosomal recessive, T cell-negative, B cell-negative, NK cell-positive 2022-07-01 criteria provided, single submitter clinical testing This sequence change replaces methionine, which is neutral and non-polar, with isoleucine, which is neutral and non-polar, at codon 183 of the RAG1 protein (p.Met183Ile). This variant is present in population databases (rs750394886, gnomAD 0.04%). This variant has not been reported in the literature in individuals affected with RAG1-related conditions. ClinVar contains an entry for this variant (Variation ID: 626003). 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 not expected to disrupt RAG1 protein function. 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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