Submissions for variant NM_000448.3(RAG1):c.2877G>A (p.Trp959Ter)

dbSNP: rs1850847819

Total submissions: 2

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
ClinGen Severe Combined Immunodeficiency Variant Curation Expert Panel, ClinGen	RCV003991481	SCV004809119	pathogenic	Recombinase activating gene 1 deficiency	2024-03-04	reviewed by expert panel	curation	The c.2877G>A (p.Trp959Ter) (NM_000448.3) variant in RAG1 is a nonsense variant that may cause a premature stop codon that is predicted to escape nonsense-mediated decay. However, it is predicted to truncate part of the core region (between aa 387-1011) critical to the function of the protein (PVS1 Met). The filtering allele frequency (the upper threshold of the 95% CI of 6/86258) of the c.2877G>A variant in RAG1 is 0.00002995 for South 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).The recombination activity assay (described in PMID 29772310) showed activity of this variant compared to wildtype RAG1 is 0 %, which is lower than the SCID VCEP threshold (<25%) for PS3_Moderate, meeting this criterion (PS3_Moderate) (Dr. Notarangelo's lab, internal communication). In summary, this variant meets the criteria to be classified as a Pathogenic variant for autosomal recessive severe combined immunodeficiency due to RAG1 deficiency based on the ACMG/AMP criteria applied, as specified by the ClinGen SCID VCEP: PVS1 Met, PM2_Supporting,PS3_Moderate (VCEP specifications version 1).
Labcorp Genetics (formerly Invitae), Labcorp	RCV001242919	SCV001416041	pathogenic	Combined immunodeficiency with skin granulomas; Severe combined immunodeficiency, autosomal recessive, T cell-negative, B cell-negative, NK cell-positive	2023-06-23	criteria provided, single submitter	clinical testing	This variant is not present in population databases (gnomAD no frequency). This sequence change creates a premature translational stop signal (p.Trp959*) in the RAG1 gene. While this is not anticipated to result in nonsense mediated decay, it is expected to disrupt the last 85 amino acid(s) of the RAG1 protein. This premature translational stop signal has been observed in individuals with clinical features of severe combined immunodeficiency (PMID: 11133745, 24290284, 24406074). ClinVar contains an entry for this variant (Variation ID: 967900). This variant disrupts a region of the RAG1 protein in which other variant(s) (p.Lys992Glu) have been determined to be pathogenic (PMID: 11313270, 18442948, 24290284). 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.