Submissions for variant NM_000536.4(RAG2):c.1247G>T (p.Trp416Leu)

dbSNP: rs193922572

Total submissions: 7

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000030396	SCV000053065	likely pathogenic	Histiocytic medullary reticulosis	2011-08-18	criteria provided, single submitter	curation	Converted during submission to Likely pathogenic.
Pediatric Immunology Service, The Chaim Sheba Medical Center at Tel HaShomer	RCV000681591	SCV000693939	uncertain significance	Histiocytic medullary reticulosis; Recombinase activating gene 2 deficiency; Inborn error of immunity	2018-03-06	criteria provided, single submitter	research
Blueprint Genetics	RCV000788782	SCV000928024	likely pathogenic	not provided	2018-10-30	criteria provided, single submitter	clinical testing
Invitae	RCV001389165	SCV001590431	pathogenic	Combined immunodeficiency with skin granulomas; Severe combined immunodeficiency, autosomal recessive, T cell-negative, B cell-negative, NK cell-positive	2023-11-10	criteria provided, single submitter	clinical testing	This sequence change replaces tryptophan, which is neutral and slightly polar, with leucine, which is neutral and non-polar, at codon 416 of the RAG2 protein (p.Trp416Leu). This variant is present in population databases (rs193922572, gnomAD 0.04%). This missense change has been observed in individual(s) with severe combined immunodeficiency (PMID: 16960852, 17572155, 30778343). ClinVar contains an entry for this variant (Variation ID: 36717). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is expected to disrupt RAG2 protein function with a positive predictive value of 95%. Experimental studies have shown that this missense change affects RAG2 function (PMID: 29772310). For these reasons, this variant has been classified as Pathogenic.
Victorian Clinical Genetics Services, Murdoch Childrens Research Institute	RCV000030396	SCV003921846	pathogenic	Histiocytic medullary reticulosis	2020-07-22	criteria provided, single submitter	clinical testing	0102 - Loss-of-function is a known mechanism of disease for this gene. (N) 0106 - This gene is known to be associated with autosomal recessive disease. (N) 0200 - Variant is predicted to result in a missense amino acid change from tryptophan to leucine (exon 3). (N) 0252 - Variant is homozygous. (N) 0304 - Variant is present in gnomAD <0.01 for a recessive condition (11 Het, 0 Hom). (P) 0501 - Missense variant consistently predicted to be damaging by multiple in-silico tools or highly conserved with a major amino acid change. (P) 0601 - Variant affects at least one well-established (essential) functional domain or motif. It is located on the edge of the PHD domain which has been shown to be essential for protein function and represents a hotspot for previously described variants in the gene (PMID20234091, Decipher) (P) 0802 - Moderate previous evidence of pathogenicity in unrelated individuals. The variant has been described in four independent patients with Omenn Syndrome or SCID, twice in ClinVar and twice in the literature (PMID29772310, Gupta 2017) (P) 1001 - Strong functional evidence supporting abnormal protein function. This variant has been shown to severely impair DH-JH and VK-JK recombination activity, as well as increase protein degradation and affect cytosolic retention (PMID20234091, 29772310) (P) 1101 - Very strong and specific phenotype match. (P) 1205 - Variant is both maternally and paternally inherited. (N)
PreventionGenetics, part of Exact Sciences	RCV003407371	SCV004114123	pathogenic	RAG2-related condition	2023-06-13	criteria provided, single submitter	clinical testing	The RAG2 c.1247G>T variant is predicted to result in the amino acid substitution p.Trp416Leu. This variant has been reported in the homozygous state in individuals with Omenn syndrome (Patient 45, Sobacchi et al. 2006. PubMed ID: 16960852; Patient 33, Tirosh et al. 2018. PubMed ID: 29772310; Patient 43, Aluri et al. 2019. PubMed ID: 30778343). Functional analyses have shown that this variant impacts protein function (Couëdel et al. 2010. PubMed ID: 20234091; Notarangelo et al. 2016. PubMed ID: 26996199; Tirosh et al. 2018. PubMed ID: 29772310). This variant is reported in 0.036% of alleles in individuals of South Asian descent in gnomAD (http://gnomad.broadinstitute.org/variant/11-36614472-C-A). Taken together, we interpret this variant as pathogenic.
Baylor Genetics	RCV003473150	SCV004200539	pathogenic	Combined immunodeficiency with skin granulomas	2023-10-04	criteria provided, single submitter	clinical testing