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: 4
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
ClinGen Severe Combined Immunodeficiency Variant Curation Expert Panel, ClinGen RCV003991479 SCV004809114 uncertain significance Recombinase activating gene 1 deficiency 2024-03-04 reviewed by expert panel curation NM_000448.3(RAG1):c.1088G>A is a missense variant predicted to cause substitution of Cysteine by Tyrosine at amino acid 363 (p.Cys363Tyr). The filtering allele frequency (the upper threshold of the 95% CI of 3/44900) of the c.1088G>A variant in RAG1 is 0.00002004 for East Asian chromosomes by gnomAD v4, which is lower than the ClinGen SCID VCEP threshold (<0.000102) for PM2_Supporting, and therefore meets this criterion (PM2_Supporting). Patient with SCID (0.5 pt.), genome sequencing conducted (0.5 pt.),T-B-NK+ lymphocyte subset profile (0.5 pt.) Total : 1.5 pts,PP4_met,PMID : 21664875. The recombination activity assay (described in PMID 29772310) showed activity of this variant compared to wildtype RAG1 is 45.3 %, (PS3_supporting) (Dr. Notarangelo lab, internal communication). This variant was found in trans with p.Arg396Cys (not yet curated by SCID VCEP; PMID : 21664875). In summary, this variant meets the criteria to be classified as a variant of uncertain significance for autosomal recessive severe combined immunodeficiency due to RAG1 deficiency based on the ACMG/AMP criteria applied, as specified by the ClinGen SCID VCEP: PM2_Supporting,PP4_met,PS3_supporting (VCEP specifications version 1).
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.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV004526088 SCV005040028 uncertain significance not specified 2024-03-07 criteria provided, single submitter clinical testing Variant summary: Variant summary: The GLA c.1088G>A (p.Arg363His) variant involves the alteration of a non-conserved nucleotide. 2/5 in silico tools predict a damaging outcome for this variant. This variant was found in 3/88023 control chromosomes (3 hemizygotes) at a frequency of 0.0000341, which does not exceed the estimated maximal expected allele frequency of a pathogenic GLA variant (0.005). This variant has been reported in multiple patients with classic or late-onset Fabry disease. In vitro enyzme activity assay showed this variant led to moderate decrease of enzyme activity. Multiple clinical diagnostic laboratories/reputable databases classified this variant as pathogenic. In addition, p.R363C and p.R363P have been reported to associate with Fabry disease, suggesting R363 is critical for GLA function. Taken together, this variant is classified as pathogenic.

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