Submissions for variant NM_000448.3(RAG1):c.691C>T (p.Gln231Ter)

Total submissions: 3

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Baylor Genetics	RCV003472555	SCV004200502	pathogenic	Combined immunodeficiency due to partial RAG1 deficiency	2023-12-11	criteria provided, single submitter	clinical testing
Labcorp Genetics (formerly Invitae), Labcorp	RCV005220720	SCV005863094	pathogenic	Combined immunodeficiency with skin granulomas; Severe combined immunodeficiency, autosomal recessive, T cell-negative, B cell-negative, NK cell-positive	2024-02-21	criteria provided, single submitter	clinical testing	This sequence change creates a premature translational stop signal (p.Gln231*) in the RAG1 gene. While this is not anticipated to result in nonsense mediated decay, it is expected to disrupt the last 813 amino acid(s) of the RAG1 protein. This variant is not present in population databases (gnomAD no frequency). This premature translational stop signal has been observed in individual(s) with RAG1-related conditions (PMID: 24144642). This variant disrupts a region of the RAG1 protein in which other variant(s) (p.Arg314Trp) have been determined to be pathogenic (PMID: 18463379, 24290284, 32445296). 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.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV005240779	SCV005883665	pathogenic	Severe combined immunodeficiency disease	2024-12-12	criteria provided, single submitter	clinical testing	Variant summary: RAG1 c.691C>T (p.Gln231X) results in a premature termination codon, predicted to cause a truncation of the encoded protein or absence of the protein due to nonsense mediated decay, which are commonly known mechanisms for disease. Truncations downstream of this position have been classified as pathogenic by our laboratory. The variant was absent in 250884 control chromosomes. c.691C>T has been reported in the literature in at least one compound heterozygous individual affected with Severe Combined Immunodeficiency (Schuetz_2014). To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. The following publication has been ascertained in the context of this evaluation (PMID: 24144642). ClinVar contains an entry for this variant (Variation ID: 2678203). Based on the evidence outlined above, the variant was classified as pathogenic.