ClinVar Miner

Submissions for variant NM_000536.4(RAG2):c.914C>T (p.Pro305Leu)

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Total submissions: 1
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Invitae RCV003061066 SCV003455076 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 proline, which is neutral and non-polar, with leucine, which is neutral and non-polar, at codon 305 of the RAG2 protein (p.Pro305Leu). This variant is present in population databases (rs756192655, gnomAD 0.002%). This variant has not been reported in the literature in individuals affected with RAG2-related conditions. ClinVar contains an entry for this variant (Variation ID: 2147765). 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 RAG2 protein function with a positive predictive value of 95%. This variant disrupts the p.Pro305 amino acid residue in RAG2. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 32655540). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. 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.

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