ClinVar Miner

Submissions for variant NM_000448.3(RAG1):c.1088G>A (p.Cys363Tyr)

gnomAD frequency: 0.00001  dbSNP: rs1461508819
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Total submissions: 2
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Invitae RCV001205082 SCV001376318 likely pathogenic Combined immunodeficiency with skin granulomas; Severe combined immunodeficiency, autosomal recessive, T cell-negative, B cell-negative, NK cell-positive 2022-10-27 criteria provided, single submitter clinical testing ClinVar contains an entry for this variant (Variation ID: 936307). 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. 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 missense change has been observed in individual(s) with atypical severe combined immunodeficiency (PMID: 21664875). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. This variant is present in population databases (no rsID available, gnomAD 0.01%). This sequence change replaces cysteine, which is neutral and slightly polar, with tyrosine, which is neutral and polar, at codon 363 of the RAG1 protein (p.Cys363Tyr).
3billion RCV002250731 SCV002521134 uncertain significance Histiocytic medullary reticulosis 2022-05-22 criteria provided, single submitter clinical testing The variant is observed at an extremely low frequency in the gnomAD v2.1.1 dataset (total allele frequency: <0.001%). Missense changes are a common disease-causing mechanism. In silico tool predictions suggest damaging effect of the variant on gene or gene product (REVEL: 0.97; 3Cnet: 3CNET). Same nucleotide change resulting in same amino acid change has been previously reported to be associated with RAG1- related disorder (PMID: 21664875), but the evidence of pathogenicity is insufficient at this time and it is reported as uncertain significancein ClinVar (VCV000936307). Therefore, this variant is classified as uncertain significanceaccording to the recommendation of ACMG/AMP guideline.

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