Submissions for variant NM_000448.3(RAG1):c.999T>A (p.Tyr333Ter)

gnomAD frequency: 0.00001  dbSNP: rs902350422

Total submissions: 3

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
ClinGen Severe Combined Immunodeficiency Variant Curation Expert Panel, ClinGen	RCV004765334	SCV005375439	pathogenic	Recombinase activating gene 1 deficiency	2024-06-14	reviewed by expert panel	curation	The c.999T>A (p.Tyr333Ter) (NM_000448.3) variant in RAG1 is a nonsense variant predicted to cause a premature stop codon in biologically-relevant-exon 2/2 leading to nonsense-mediated decay in a gene in which loss-of-function is an established disease mechanism (PVS1).The highest population minor allele frequency in gnomAD v4 is 0.00001470 (1/68026 alleles) in European (Non-Finnish) population, which is lower than the ClinGen SCID VCEP threshold (<0.000102) for PM2_Supporting, meeting this criterion (PM2_Supporting). Patient OM8 in PMID 11313270 has the c.999T>A (p.Tyr333Ter) variant in trans with a frameshift variant (1pt, PM3). 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,PM2_supporting,PM3 (VCEP specifications version 1).
GeneDx	RCV000521773	SCV000617481	pathogenic	not provided	2017-09-26	criteria provided, single submitter	clinical testing	The Y333X variant in the RAG1 gene has been reported previously, along with another variant, in association with Omenn syndrome (Corneo et al., 2001). This variant is predicted to cause loss of normal protein function through protein truncation. Functional studies showed dramatically reduced recombination frequency in affected cells compared to wild type (Corneo et al., 2001). The Y333X variant is not observed in large population cohorts (Lek et al., 2016). We interpret Y333X as a pathogenic variant.
Labcorp Genetics (formerly Invitae), Labcorp	RCV003766940	SCV004570839	pathogenic	Combined immunodeficiency with skin granulomas; Severe combined immunodeficiency, autosomal recessive, T cell-negative, B cell-negative, NK cell-positive	2023-09-29	criteria provided, single submitter	clinical testing	This sequence change creates a premature translational stop signal (p.Tyr333*) in the RAG1 gene. While this is not anticipated to result in nonsense mediated decay, it is expected to disrupt the last 711 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 Omenn syndrome (PMID: 11313270). ClinVar contains an entry for this variant (Variation ID: 449383). This variant disrupts a region of the RAG1 protein in which other variant(s) (p.His994Arg) have been determined to be pathogenic (PMID: 33193364; Invitae). 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.