Submissions for variant NM_000448.3(RAG1):c.2459A>G (p.Lys820Arg)

gnomAD frequency: 0.12928  dbSNP: rs2227973

Total submissions: 13

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
ClinGen Severe Combined Immunodeficiency Variant Curation Expert Panel, ClinGen	RCV003492019	SCV004242264	benign	Recombinase activating gene 1 deficiency	2024-01-23	reviewed by expert panel	curation	The NM_000448.3:c.2459A>G variant in RAG1 is a missense variant predicted to cause the substitution of Lysine by Arginine at amino acid 820 (p.Lys820Arg). The filtering allele frequency (the lower threshold of the 95% CI of 26338/44862) of the c.2459A>G variant in RAG1 is 0.5818 for East Asian chromosomes by gnomAD v.4, which is higher than the ClinGen SCID VCEP threshold (>0.00872) for BA1, and therefore meets this criterion (BA1). Additionally, 22786 homozygous adults are reported on gnomAD v.4, BS2_Supporting is Met. In summary, this variant meets the criteria to be classified as Benign for autosomal recessive SCID. ACMG/AMP criteria applied, as specified by the ClinGen SCID-VCEP: BA1 and BS2_Supporting. (VCEP specifications version 1).
PreventionGenetics, part of Exact Sciences	RCV000245314	SCV000304366	benign	not specified		criteria provided, single submitter	clinical testing
Illumina Laboratory Services, Illumina	RCV000385043	SCV000371686	benign	Histiocytic medullary reticulosis	2018-03-06	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	RCV000290555	SCV000371687	benign	Severe combined immunodeficiency, autosomal recessive, T cell-negative, B cell-negative, NK cell-positive	2018-03-06	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.
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	RCV000245314	SCV000540148	benign	not specified	2016-03-28	criteria provided, single submitter	clinical testing	Variant identified in a genome or exome case(s) and assessed due to predicted null impact of the variant or pathogenic assertions in the literature or databases. Disclaimer: This variant has not undergone full assessment. The following are preliminary notes: Frequency - papers in HGMD do not provide evidence of disease association
Labcorp Genetics (formerly Invitae), Labcorp	RCV001512872	SCV001720364	benign	Combined immunodeficiency with skin granulomas; Severe combined immunodeficiency, autosomal recessive, T cell-negative, B cell-negative, NK cell-positive	2024-02-01	criteria provided, single submitter	clinical testing
GeneDx	RCV001636747	SCV001852445	benign	not provided	2015-03-03	criteria provided, single submitter	clinical testing	This variant is associated with the following publications: (PMID: 16857995, 24290284, 22424479, 21625022)
Genome-Nilou Lab	RCV001795396	SCV002033423	benign	Combined immunodeficiency with skin granulomas	2021-11-07	criteria provided, single submitter	clinical testing
Genome-Nilou Lab	RCV000385043	SCV002033424	benign	Histiocytic medullary reticulosis	2021-11-07	criteria provided, single submitter	clinical testing
Genome-Nilou Lab	RCV000290555	SCV002033425	benign	Severe combined immunodeficiency, autosomal recessive, T cell-negative, B cell-negative, NK cell-positive	2021-11-07	criteria provided, single submitter	clinical testing
GreenArray Genomic Research & Solutions of Accurate Diagnostic Private Limited	RCV001814976	SCV002061920	benign	Immunodeficiency 104		criteria provided, single submitter	clinical testing	The variant is predicted to be benign by PolyPhen2 and the residue is conserved across species. The amino acid change p.Lys820Arg in RAG1
Unidad de Genómica Garrahan, Hospital de Pediatría Garrahan	RCV000245314	SCV004233912	benign	not specified	2024-01-24	criteria provided, single submitter	clinical testing	This variant is classified as Benign based on local population frequency. This variant was detected in 48% of patients studied by a panel of primary immunodeficiencies. Number of patients: 42. Only high quality variants are reported.
Breakthrough Genomics, Breakthrough Genomics	RCV001636747	SCV005316149	benign	not provided		criteria provided, single submitter	not provided