ClinVar Miner

Submissions for variant NM_000536.4(RAG2):c.1268G>A (p.Cys423Tyr)

gnomAD frequency: 0.00001  dbSNP: rs768567592
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Total submissions: 2
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Invitae RCV000645685 SCV000767436 pathogenic Combined immunodeficiency with skin granulomas; Severe combined immunodeficiency, autosomal recessive, T cell-negative, B cell-negative, NK cell-positive 2023-11-24 criteria provided, single submitter clinical testing This sequence change replaces cysteine, which is neutral and slightly polar, with tyrosine, which is neutral and polar, at codon 423 of the RAG2 protein (p.Cys423Tyr). This variant is present in population databases (rs768567592, gnomAD 0.003%). This missense change has been observed in individual(s) with clinical features of 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. ClinVar contains an entry for this variant (Variation ID: 536960). 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%. For these reasons, this variant has been classified as Pathogenic.
Natera, Inc. RCV001835894 SCV002090433 uncertain significance Histiocytic medullary reticulosis 2021-08-16 no assertion criteria provided clinical testing

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