Submissions for variant NM_000536.4(RAG2):c.22G>A (p.Val8Ile)

gnomAD frequency: 0.00313  dbSNP: rs150762709

Total submissions: 9

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
ClinGen Severe Combined Immunodeficiency Variant Curation Expert Panel, ClinGen	RCV003398750	SCV004102763	likely benign	Recombinase activating gene 2 deficiency	2023-11-14	reviewed by expert panel	curation	The NM_000536.4:c.22G>A variant in RAG2 is a missense variant predicted to cause substitution of valine by isoleucine at amino acid 8 (p.Val8Ile). This variant has a population max filtering allele frequency of 0.004397 in gnomAD, which is above the threshold for BS1 set by the ClinGen SCID VCEP for RAG2 (>0.00195). This variant has not been identified in individuals with SCID, though it has been identified in one individual with CID (PMID: 28769923) who carried a co-occurring variant p.D200H (phase unknown, p.D200H not curated by ClinGen SCID VCEP). In addition, this variant is present in 5 homozygotes in gnomAD (BS2_Supporting). In summary, this variant is classified as a Likely Benign for autosomal recessive SCID based on the ACMG criteria applied: BS1 and BS2_Supporting as specified by the ClinGen SCID VCEP (VCEP specifications version 1).
Illumina Laboratory Services, Illumina	RCV000388047	SCV000371806	likely 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 likely benign is not then subjected to further curation. The score for this variant resulted in a classification of likely benign for this disease.
Illumina Laboratory Services, Illumina	RCV000277572	SCV000371807	likely 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 likely benign is not then subjected to further curation. The score for this variant resulted in a classification of likely benign for this disease.
Invitae	RCV000645694	SCV000767445	benign	Combined immunodeficiency with skin granulomas; Severe combined immunodeficiency, autosomal recessive, T cell-negative, B cell-negative, NK cell-positive	2024-01-31	criteria provided, single submitter	clinical testing
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	RCV001705920	SCV001473581	benign	not provided	2023-10-26	criteria provided, single submitter	clinical testing
Genome-Nilou Lab	RCV000277572	SCV001716369	benign	Histiocytic medullary reticulosis	2021-05-18	criteria provided, single submitter	clinical testing
Natera, Inc.	RCV000277572	SCV001456099	benign	Histiocytic medullary reticulosis	2020-09-16	no assertion criteria provided	clinical testing
Genome Diagnostics Laboratory, University Medical Center Utrecht	RCV001705920	SCV001930376	likely benign	not provided		no assertion criteria provided	clinical testing
Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	RCV001705920	SCV001963629	likely benign	not provided		no assertion criteria provided	clinical testing