Submissions for variant NM_000448.3(RAG1):c.251A>G (p.His84Arg)

gnomAD frequency: 0.00550  dbSNP: rs150199231

Total submissions: 6

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
ClinGen Severe Combined Immunodeficiency Variant Curation Expert Panel, ClinGen	RCV003492038	SCV004242265	benign	Recombinase activating gene 1 deficiency	2024-01-23	reviewed by expert panel	curation	The NM_000448.3:c.251A>G variant in RAG1 is a missense variant predicted to cause the substitution of Histidine by Arginine at amino acid 249 (p.His84Arg). The Popmax Filtering allele frequency (95% CI) of the c.251A>G variant in RAG1 is 0.01622 in gnomAD v.4, which is higher than the ClinGen SCID VCEP threshold (>0.00872) for BA1. Therefore, BA1 is met. Additionally, 19 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).
GeneDx	RCV000423103	SCV000514366	benign	not specified	2015-06-23	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.
Labcorp Genetics (formerly Invitae), Labcorp	RCV000645695	SCV000767446	benign	Combined immunodeficiency with skin granulomas; Severe combined immunodeficiency, autosomal recessive, T cell-negative, B cell-negative, NK cell-positive	2025-01-23	criteria provided, single submitter	clinical testing
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	RCV003736759	SCV004562852	benign	not provided	2023-11-28	criteria provided, single submitter	clinical testing
Breakthrough Genomics, Breakthrough Genomics	RCV003736759	SCV005316142	benign	not provided		criteria provided, single submitter	not provided
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000423103	SCV005380605	benign	not specified	2024-08-30	criteria provided, single submitter	clinical testing	Variant summary: RAG1 c.251A>G (p.His84Arg) results in a non-conservative amino acid change located in the RAG1 importin-binding domain (IPR035714) of the encoded protein sequence. Two of four in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 0.0011 in 251076 control chromosomes, predominantly at a frequency of 0.016 within the African or African-American subpopulation in the gnomAD database, including 4 homozygotes. The observed variant frequency within African or African-American control individuals in the gnomAD database is approximately 10 fold of the estimated maximal expected allele frequency for a pathogenic variant in RAG1 causing Severe Combined Immunodeficiency phenotype (0.0016). To our knowledge, no occurrence of c.251A>G 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: 378467). Based on the evidence outlined above, the variant was classified as benign.