ClinVar Miner

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

dbSNP: rs1590713653
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Total submissions: 7
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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
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV004526778 SCV005039738 uncertain significance not specified 2024-03-19 criteria provided, single submitter clinical testing Variant summary: RAG2 c.1396C>T (p.Leu466Phe) results in a non-conservative amino acid change located in the Recombination activating protein 2, PHD domain (IPR025162) of the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant was absent in 251482 control chromosomes. The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. To our knowledge, no occurrence of c.1396C>T in individuals affected with Severe Combined Immunodeficiency and no experimental evidence demonstrating its impact on protein function have been reported. ClinVar contains an entry for this variant (Variation ID: 650904). Based on the evidence outlined above, the variant was classified as uncertain significance.
Natera, Inc. RCV001104242 SCV002090388 uncertain significance Histiocytic medullary reticulosis 2021-08-24 no assertion criteria provided clinical testing

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