ClinVar Miner

Submissions for variant NM_000448.3(RAG1):c.2125G>A (p.Gly709Ser)

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Total submissions: 1
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Labcorp Genetics (formerly Invitae), Labcorp RCV003790463 SCV004580238 likely pathogenic Combined immunodeficiency with skin granulomas; Severe combined immunodeficiency, autosomal recessive, T cell-negative, B cell-negative, NK cell-positive 2024-05-13 criteria provided, single submitter clinical testing This sequence change replaces glycine, which is neutral and non-polar, with serine, which is neutral and polar, at codon 709 of the RAG1 protein (p.Gly709Ser). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with Omenn syndrome (PMID: 32655540). 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. This variant disrupts the p.Gly709 amino acid residue in RAG1. Other variant(s) that disrupt this residue have been observed in individuals with RAG1-related conditions (PMID: 16960852; Invitae), which suggests that this may be a clinically significant amino acid residue. 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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