ClinVar Miner

Submissions for variant NM_000448.3(RAG1):c.940C>T (p.Arg314Trp)

dbSNP: rs121918568
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Total submissions: 3
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Baylor Genetics RCV003473095 SCV004200531 pathogenic Combined immunodeficiency due to partial RAG1 deficiency 2022-06-22 criteria provided, single submitter clinical testing
Labcorp Genetics (formerly Invitae), Labcorp RCV003764571 SCV004576471 likely pathogenic Combined immunodeficiency with skin granulomas; Severe combined immunodeficiency, autosomal recessive, T cell-negative, B cell-negative, NK cell-positive 2024-02-06 criteria provided, single submitter clinical testing This sequence change replaces arginine, which is basic and polar, with tryptophan, which is neutral and slightly polar, at codon 314 of the RAG1 protein (p.Arg314Trp). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with atypical severe combined immunodeficiency and/or combined immunodeficiency (PMID: 18463379, 32445296). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. ClinVar contains an entry for this variant (Variation ID: 13156). 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 with a negative predictive value of 80%. Experimental studies have shown that this missense change affects RAG1 function (PMID: 18463379, 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.
OMIM RCV000014042 SCV000034289 pathogenic Combined immunodeficiency with skin granulomas 2008-05-08 no assertion criteria provided literature only

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