Submissions for variant NM_000536.4(RAG2):c.1158C>A (p.Phe386Leu)

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Total submissions: 15

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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	RCV003398751	SCV004102762	benign	Recombinase activating gene 2 deficiency	2023-11-14	reviewed by expert panel	curation	The NM_000536.4:c.1158C>A variant in RAG2 is a missense variant predicted to cause substitution of phenylalanine by leucine at amino acid 386 (p.Phe386Leu). This variant has a population max filtering allele frequency of 0.01649 in the European (non-Finnish) population in gnomAD, which is above the threshold for BA1 set by the ClinGen SCID VCEP for RAG2 (>0.00872). In addition, this variant is present in 23 homozygotes in gnomAD (BS2_Supporting). In summary, this variant meets the criteria to be classified as Benign for autosomal recessive SCID based on the ACMG criteria applied: BA1 and BS2_Supporting as specified by the ClinGen SCID VCEP (VCEP specifications version 1).
Mayo Clinic Laboratories, Mayo Clinic	RCV000127714	SCV007302247	benign	not specified	2024-11-04	criteria provided, single submitter	clinical testing	BS1, BS2, PP3
Breakthrough Genomics, Breakthrough Genomics	RCV001701521	SCV005224215	likely benign	not provided		criteria provided, single submitter	not provided
CeGaT Center for Human Genetics Tuebingen	RCV001701521	SCV004010064	benign	not provided	2025-09-01	criteria provided, single submitter	clinical testing	RAG2: BS1, BS2
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000127714	SCV001363005	benign	not specified	2019-09-10	criteria provided, single submitter	clinical testing	Variant summary: RAG2 c.1158C>A (p.Phe386Leu) results in a non-conservative amino acid change in the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 0.0097 in 251334 control chromosomes, predominantly at a frequency of 0.017 within the Non-Finnish European subpopulation in the gnomAD database, including 21 homozygotes. The observed variant frequency within Non-Finnish European control individuals in the gnomAD database is approximately 24 fold of the estimated maximal expected allele frequency for a pathogenic variant in RAG2 causing Severe Combined Immunodeficiency Syndrome phenotype (0.00071), strongly suggesting that the variant is a benign polymorphism found primarily in populations of Non-Finnish European origin. At least one publication reports experimental evidence evaluating an impact on protein function. This report suggests that the variant showed similar levels of recombination activity compared to that of wild-type (Tirosh_2019). Three ClinVar submitters (evaluation after 2014) cite the variant as benign (2x) and once as likely benign. Based on the evidence outlined above, the variant was classified as benign.
Illumina Laboratory Services, Illumina	RCV001107016	SCV001264141	benign	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 and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease.
Illumina Laboratory Services, Illumina	RCV001107015	SCV001264140	benign	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 and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease.
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	RCV001701521	SCV001157038	benign	not provided	2024-12-19	criteria provided, single submitter	clinical testing
Pediatric Immunology Service, The Chaim Sheba Medical Center at Tel HaShomer	RCV000681590	SCV000693938	benign	Recombinase activating gene 2 deficiency; Inborn error of immunity	2018-03-06	criteria provided, single submitter	research
Labcorp Genetics (formerly Invitae), Labcorp	RCV000551519	SCV000646378	benign	Combined immunodeficiency with skin granulomas; Severe combined immunodeficiency, autosomal recessive, T cell-negative, B cell-negative, NK cell-positive	2026-02-02	criteria provided, single submitter	clinical testing
GeneDx	RCV000127714	SCV000171293	benign	not specified	2012-11-26	criteria provided, single submitter	clinical testing	This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease.
Natera, Inc.	RCV001107016	SCV002090444	likely benign	Histiocytic medullary reticulosis	2019-11-12	no assertion criteria provided	clinical testing
Genome Diagnostics Laboratory, University Medical Center Utrecht	RCV001701521	SCV001928854	likely benign	not provided		no assertion criteria provided	clinical testing
Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	RCV000127714	SCV001742902	benign	not specified		no assertion criteria provided	clinical testing
Counsyl	RCV000670144	SCV000794963	likely benign	Combined immunodeficiency with skin granulomas; Histiocytic medullary reticulosis; Severe combined immunodeficiency, autosomal recessive, T cell-negative, B cell-negative, NK cell-positive	2017-10-24	no assertion criteria provided	clinical testing	This submission and the accompanying classification are no longer maintained by the submitter. For more information on current observations and classification, please contact variantquestions@myriad.com.

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