ClinVar Miner

Submissions for variant NM_000536.4(RAG2):c.955G>T (p.Gly319Ter)

dbSNP: rs879541124
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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 RCV003403398 SCV004102760 likely pathogenic Recombinase activating gene 2 deficiency 2023-11-14 reviewed by expert panel curation The NM_000536.4:c.955G>T variant in RAG2 is a nonsense variant predicted to result in a truncated protein (p.Gly319*). Although this variant is expected to escape nonsense-mediated decay (NMD), it would be expected to disrupt approximately 40% of the RAG2 protein. In addition, this variant would be expected to disrupt/remove the entire PHD domain (amino acids 414-487), which is defined as a mutational hotspot/critical functional domain by the ClinGen SCID VCEP (PMID: 15964836). PVS1 met. This variant is absent from gnomAD v2.1.1 (PM2_Supporting). To our knowledge, the variant has not been identified in the literature in patients/case reports or functional studies. In summary, this variant meets the criteria to be classified as Likely Pathogenic for autosomal recessive SCID based on the ACMG/AMP criteria applied, as specified by the ClinGen SCID VCEP: PM2 and PVS1 (VCEP specifications version 1).
Eurofins Ntd Llc (ga) RCV000595625 SCV000706444 pathogenic not provided 2017-02-21 criteria provided, single submitter clinical testing
Invitae RCV001220628 SCV001392631 pathogenic Combined immunodeficiency with skin granulomas; Severe combined immunodeficiency, autosomal recessive, T cell-negative, B cell-negative, NK cell-positive 2023-10-20 criteria provided, single submitter clinical testing This sequence change creates a premature translational stop signal (p.Gly319*) in the RAG2 gene. While this is not anticipated to result in nonsense mediated decay, it is expected to disrupt the last 209 amino acid(s) of the RAG2 protein. This variant is not present in population databases (gnomAD no frequency). This variant has not been reported in the literature in individuals affected with RAG2-related conditions. ClinVar contains an entry for this variant (Variation ID: 500475). This variant disrupts a region of the RAG2 protein in which other variant(s) (p.His468Argfs*16, p.Arg523Glufs*49, p.Glu480*) have been determined to be pathogenic (PMID: 21624848, 24144642, 26915675). This suggests that this is a clinically significant region of the protein, and that variants that disrupt it are likely to be disease-causing. For these reasons, this variant has been classified as Pathogenic.
Baylor Genetics RCV003465344 SCV004206068 likely pathogenic Combined immunodeficiency with skin granulomas 2022-10-03 criteria provided, single submitter clinical testing

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