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

gnomAD frequency: 0.00001  dbSNP: rs1461508819

Total submissions: 4

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).
Labcorp Genetics (formerly Invitae), Labcorp	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	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. 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). This variant is present in population databases (no rsID available, gnomAD 0.01%). 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. ClinVar contains an entry for this variant (Variation ID: 936307). 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.
3billion, Medical Genetics	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: RAG1 c.1088G>A (p.Cys363Tyr) results in a non-conservative amino acid change located in the V(D)J recombination-activating protein 1, Zinc finger (IPR023336) of the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 8e-06 in 251272 control chromosomes. c.1088G>A has been reported in the literature in individuals affected with Severe Combined Immunodeficiency (Felgentreff_2011). These data do not allow any conclusion about variant significance. At least one publication reports experimental evidence evaluating an impact on protein function showing decreased V(D)J activity (Schuetz_2023). The following publications have been ascertained in the context of this evaluation (PMID: 21664875, 36279417). ClinVar contains an entry for this variant (Variation ID: 936307). Based on the evidence outlined above, the variant was classified as VUS-possibly pathogenic.