ClinVar Miner

Submissions for variant NM_000448.3(RAG1):c.1361T>A (p.Leu454Gln)

dbSNP: rs199474677
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Total submissions: 3
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Invitae RCV000819860 SCV000960543 likely pathogenic Combined immunodeficiency with skin granulomas; Severe combined immunodeficiency, autosomal recessive, T cell-negative, B cell-negative, NK cell-positive 2023-12-04 criteria provided, single submitter clinical testing This sequence change replaces leucine, which is neutral and non-polar, with glutamine, which is neutral and polar, at codon 454 of the RAG1 protein (p.Leu454Gln). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with Omenn syndrome and/or severe combined immunodeficiency (PMID: 21624848, 34664192). ClinVar contains an entry for this variant (Variation ID: 68682). 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) has been performed at Invitae for this missense variant, however the output from this modeling did not meet the statistical confidence thresholds required to predict the impact of this variant on RAG1 protein function. Experimental studies have shown that this missense change affects RAG1 function (PMID: 24290284). 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.
GeneDx RCV000059563 SCV003805456 likely pathogenic not provided 2023-02-22 criteria provided, single submitter clinical testing Published functional studies suggest a damaging effect on recombination activity (Lee et al., 2014); Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 21624848, 24290284, 29051008, 34664192, 15242397, 19396172, 26996199, 11971977, 27825771, 32311393, 35487367)
UniProtKB/Swiss-Prot RCV000059563 SCV000091095 not provided not provided no assertion provided not provided

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