Submissions for variant NM_000536.4(RAG2):c.1396C>T (p.Leu466Phe)

dbSNP: rs1590713653

Total submissions: 6

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
ClinGen Severe Combined Immunodeficiency Variant Curation Expert Panel, ClinGen	RCV003492174	SCV004242270	likely pathogenic	Recombinase activating gene 2 deficiency	2024-01-23	reviewed by expert panel	curation	The c.1396C>T (NM_000536.4) variant in RAG2 is a missense variant predicted to cause the substitution of Leucine by Phenylalanine at amino acid 466 (p.Leu466Phe). This variant is absent from gnomAD v2.1.1 (PM2_Supporting). This variant is located in the PHD domain, amino acids 414-487 of RAG2, which is defined as a critical functional domain by the ClinGen SCID VCEP (PMID: 26996199); PM1_Moderate. One patient from Invitae presents carries this variant in trans with c.1352G>C (p.Gly451Ala) (classified as Likely Pathogenic according to SCID VCEP specifications). The parents were also tested; each was heterozygous for one variant - variants are in trans. 1 point, PM3 is met. The patient carrying this variant presents: T-B-NK+ lymphocyte subset profile 0.5 pts + SCID gene panel or exome/genome sequencing conducted 0.5 pts; + Diagnostic criteria for SCID/Leaky SCID/Omenn syndrome 0.5 pts; Total is 1.5 points, PP4 is met. In summary, this variant meets the criteria to be classified as Likely Pathogenic for autosomal recessive recombinase activating gene 2 deficiency based on the ACMG/AMP criteria applied, as specified by the ClinGen SCID VCEP. Criteria applied: PM2_Supporting, PM1_Moderate, PP4, and PM3 (VCEP specifications version 1.0).
Invitae	RCV000806149	SCV000946131	likely pathogenic	Combined immunodeficiency with skin granulomas; Severe combined immunodeficiency, autosomal recessive, T cell-negative, B cell-negative, NK cell-positive	2022-12-22	criteria provided, single submitter	clinical testing	This sequence change replaces leucine, which is neutral and non-polar, with phenylalanine, which is neutral and non-polar, at codon 466 of the RAG2 protein (p.Leu466Phe). This variant is not present in population databases (gnomAD no frequency). In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic. 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. ClinVar contains an entry for this variant (Variation ID: 650904). This missense change has been observed in individual(s) with clinical features of RAG2-related conditions (Invitae). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant.
Illumina Laboratory Services, Illumina	RCV001104241	SCV001261091	uncertain significance	Severe combined immunodeficiency, autosomal recessive, T cell-negative, B cell-negative, NK cell-positive	2018-01-13	criteria provided, single submitter	clinical testing	This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score, this variant could not be ruled out of causing disease and therefore its association with disease required further investigation. A literature search was performed for the gene, cDNA change, and amino acid change (if applicable). No publications were found based on this search. This variant was therefore classified as a variant of unknown significance for this disease.
Illumina Laboratory Services, Illumina	RCV001104242	SCV001261092	uncertain significance	Histiocytic medullary reticulosis	2018-01-13	criteria provided, single submitter	clinical testing	This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score, this variant could not be ruled out of causing disease and therefore its association with disease required further investigation. A literature search was performed for the gene, cDNA change, and amino acid change (if applicable). No publications were found based on this search. This variant was therefore classified as a variant of unknown significance for this disease.
Mayo Clinic Laboratories, Mayo Clinic	RCV003480843	SCV004225392	uncertain significance	not provided	2022-10-18	criteria provided, single submitter	clinical testing	PM2_supporting
Natera, Inc.	RCV001104242	SCV002090388	uncertain significance	Histiocytic medullary reticulosis	2021-08-24	no assertion criteria provided	clinical testing