ClinVar Miner

Submissions for variant NM_000448.3(RAG1):c.527G>T (p.Cys176Phe)

gnomAD frequency: 0.00002  dbSNP: rs149229197
Minimum review status: Collection method:
Minimum conflict level:
ClinVar version:
Total submissions: 5
Download table as spreadsheet
Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
ClinGen Severe Combined Immunodeficiency Variant Curation Expert Panel, ClinGen RCV003401396 SCV004102809 uncertain significance Recombinase activating gene 1 deficiency 2023-11-14 reviewed by expert panel curation The c.527G>T (NM_000448.3) variant in RAG1 is a missense variant predicted to cause a substitution of Cysteine by Phenylalanine at amino acid 176 (p.Cys176Phe). The filtering allele frequency (the upper threshold of the 95% CI of 3/128742) of the c.527G>T variant in RAG1 is 0.000002930 for European (non-Finnish) chromosomes by gnomAD v2.1.1, which is lower than the ClinGen SCID VCEP threshold (<0.000102) for PM2_Supporting, and therefore meets this criterion (PM2_Supporting). This variant has been detected in at least two individuals with SCID and Leaky SCID who are homozygous for the variant (1 pt, PM3; PMID: 28769923 and 34539671). At least one patient with this variant displayed Diagnostic criteria for Leaky SCID (0.5pts) + SCID gene panel (0.5pts) + T-B-NK+ lymphocyte subset profile (0.5 pts), total 1.5 points, PP4 met (PMID: 34539671). In summary, this variant meets the criteria to be classified as Uncertain significance for autosomal recessive SCID based on the ACMG/AMP criteria applied, PM2_Supporting, PM3, and PP4, as specified by the ClinGen SCID VCEP (VCEP specifications version 1).
GeneDx RCV000413643 SCV000490762 likely pathogenic not provided 2016-04-29 criteria provided, single submitter clinical testing To our knowledge, the C176F missense variant has neither been published as a pathogenic variant, norreported as a benign polymorphism. C176F represents a non-conservative amino acid substitution as apolar Cysteine residue is replaced with a non-polar Phenylalanine residue; the loss of the Cysteine residuecould also affect normal disulfide bond formation in the protein. In addition, the position in the RAG1protein where this substitution occurs is highly conserved among species. Therefore, C176F is a strongcandidate for a pathogenic variant; however, the possibility that it is a benign variant cannot beexcluded.
Labcorp Genetics (formerly Invitae), Labcorp RCV000792591 SCV000931897 pathogenic Combined immunodeficiency with skin granulomas; Severe combined immunodeficiency, autosomal recessive, T cell-negative, B cell-negative, NK cell-positive 2024-09-02 criteria provided, single submitter clinical testing This sequence change replaces cysteine, which is neutral and slightly polar, with phenylalanine, which is neutral and non-polar, at codon 176 of the RAG1 protein (p.Cys176Phe). This variant is present in population databases (rs149229197, gnomAD 0.002%). This missense change has been observed in individual(s) with severe combined immunodeficiency (SCID) and delayed onset combined immunodeficiency with autoimmune/granulomatous manifestations (CID-G/AI) (PMID: 26457731, 28769923; internal data). ClinVar contains an entry for this variant (Variation ID: 372487). Invitae Evidence 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 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. For these reasons, this variant has been classified as Pathogenic.
Baylor Genetics RCV003476000 SCV004200521 likely pathogenic Combined immunodeficiency due to partial RAG1 deficiency 2023-11-10 criteria provided, single submitter clinical testing
Fulgent Genetics, Fulgent Genetics RCV005044625 SCV005683451 likely pathogenic Combined immunodeficiency due to partial RAG1 deficiency; Combined immunodeficiency with skin granulomas; Histiocytic medullary reticulosis; Severe combined immunodeficiency, autosomal recessive, T cell-negative, B cell-negative, NK cell-positive 2024-03-26 criteria provided, single submitter clinical testing

The information on this website is not intended for direct diagnostic use or medical decision-making without review by a genetics professional. Individuals should not change their health behavior solely on the basis of information contained on this website. Neither the University of Utah nor the National Institutes of Health independently verfies the submitted information. If you have questions about the information contained on this website, please see a health care professional.