ClinVar Miner

Submissions for variant NM_000448.3(RAG1):c.2954A>G (p.Tyr985Cys)

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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 RCV005229393 SCV005868656 likely pathogenic Combined immunodeficiency with skin granulomas; Severe combined immunodeficiency, autosomal recessive, T cell-negative, B cell-negative, NK cell-positive 2024-07-17 criteria provided, single submitter clinical testing This sequence change replaces tyrosine, which is neutral and polar, with cysteine, which is neutral and slightly polar, at codon 985 of the RAG1 protein (p.Tyr985Cys). This variant is present in population databases (rs748811869, gnomAD 0.003%). This missense change has been observed in individual(s) with severe combined immunodeficiency (Invitae). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. 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 RAG1 protein function with a positive predictive value of 95%. 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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