Submissions for variant NM_000536.4(RAG2):c.2T>C (p.Met1Thr)

dbSNP: rs1554947410

Total submissions: 3

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
ClinGen Severe Combined Immunodeficiency Variant Curation Expert Panel, ClinGen	RCV003991474	SCV004809144	uncertain significance	Recombinase activating gene 2 deficiency	2024-02-20	reviewed by expert panel	curation	NM_000536.4(RAG2):c.2T>C is a missense variant predicted to cause substitution of Methionine by Threonine at amino acid 1 (p.Met1Thr). The next possible initiation codon is at codon 5. This region does not contain known pathogenic/likely pathogenic variants (PVS1_Supporting). This missense variant is located in the core domain (amino acids 1-383) (PM1_supporting). The variant is absent in gnomAD v4 (PM2_supporting). To our knowledge, this variant has not been reported in the literature in individuals affected with RAG2 related conditions or in functional studies. In summary, this variant meets the criteria to be classified as a variant of uncertain significance for autosomal recessive severe combined immunodeficiency due to RAG2 deficiency based on the ACMG/AMP criteria applied, as specified by the ClinGen SCID VCEP: PVS1_Supporting, PM1_supporting, PM2_supporting (VCEP specifications version 1).
GeneDx	RCV000579362	SCV000680578	pathogenic	not provided	2020-06-04	criteria provided, single submitter	clinical testing	Initiation codon variant in a gene for which loss-of-function is a known mechanism of disease; Not observed in large population cohorts (Lek et al., 2016)
Pediatric Immunology Service, The Chaim Sheba Medical Center at Tel HaShomer	RCV000681570	SCV000693918	likely pathogenic	Recombinase activating gene 2 deficiency; Inborn error of immunity	2018-03-06	criteria provided, single submitter	research