Submissions for variant NM_000536.4(RAG2):c.130G>T (p.Gly44Ter)

dbSNP: rs1440633758

Total submissions: 4

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
ClinGen Severe Combined Immunodeficiency Variant Curation Expert Panel, ClinGen	RCV003401875	SCV004102755	pathogenic	Recombinase activating gene 2 deficiency	2023-11-14	reviewed by expert panel	curation	The NM_000536.4:c.130G>T variant in RAG2 is a nonsense variant predicted to result in a truncated protein (p.Gly44*). Although this variant is expected to escape nonsense mediated decay (NMD), it would be expected to disrupt approximately 91% of the total RAG2 protein (would remove 484 / 528 amino acids). In addition, it would remove the entire PHD domain (amino acids 414-487), which is defined by the SCID VCEP as a region critical to RAG2 protein function (PMID: 15964836). Therefore PVS1 is met. This variant has an allele frequency of 0.000008792 in the European (non-Finnish) population in gnomAD, which is below the threshold for max filtering allele frequency for PM2_Supporting set by the ClinGen SCID VCEP for RAG2 (<0.0000588). This variant has not been reported in individuals with SCID in a peer-reviewed publication; however, it has been reported in an infant with typical SCID in a pre-print research article by Alizadeh et al (DOI: https://doi.org/10.21203/rs.3.rs-1728908/v1). The was identified via WES (0.5p) in an infant with T-NK+ typical SCID (0.5p) from a consanguineous family with a family history of SCID (0.5p) meeting the ClinGen SCID VCEP's criteria for PP4 (1.5p). The variant was homozygous in the affected infant and heterozygous in the parents (0.5p, PM3_supporting). In addition, a different frameshift variant (NM_000536.4:c.829dup p.Tyr277Leufs*4) that occurs downstream of this variant has been classified as LP by the ClinGen SCID VCEP. In summary, this variant meets the criteria to be classified as Pathogenic for autosomal recessive SCID based on the ACMG criteria applied: PVS1, PM2_Supporting, PP4, and PM3_Supporting as specified by the ClinGen SCID VCEP (VCEP specifications version 1).
Labcorp Genetics (formerly Invitae), Labcorp	RCV001943182	SCV002184685	pathogenic	Combined immunodeficiency with skin granulomas; Severe combined immunodeficiency, autosomal recessive, T cell-negative, B cell-negative, NK cell-positive	2022-09-07	criteria provided, single submitter	clinical testing	For these reasons, this variant has been classified as Pathogenic. This variant disrupts a region of the RAG2 protein in which other variant(s) (p.Arg148*) have been determined to be pathogenic (PMID: 11133745, 28600779, 30307608). This suggests that this is a clinically significant region of the protein, and that variants that disrupt it are likely to be disease-causing. ClinVar contains an entry for this variant (Variation ID: 1412375). This variant has not been reported in the literature in individuals affected with RAG2-related conditions. This variant is present in population databases (no rsID available, gnomAD 0.0009%). This sequence change creates a premature translational stop signal (p.Gly44*) in the RAG2 gene. While this is not anticipated to result in nonsense mediated decay, it is expected to disrupt the last 484 amino acid(s) of the RAG2 protein.
Baylor Genetics	RCV003471043	SCV004206075	likely pathogenic	Combined immunodeficiency with skin granulomas	2021-12-20	criteria provided, single submitter	clinical testing
GeneDx	RCV004774534	SCV005385699	likely pathogenic	not provided	2024-02-02	criteria provided, single submitter	clinical testing	Nonsense variant predicted to result in protein truncation, as the last 484 amino acids are lost, and other loss-of-function variants have been reported downstream in HGMD; Not observed at significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 37516813)