Submissions for variant NM_000448.3(RAG1):c.725A>G (p.Gln242Arg)

gnomAD frequency: 0.00164  dbSNP: rs76897604

Total submissions: 8

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
ClinGen Severe Combined Immunodeficiency Variant Curation Expert Panel, ClinGen	RCV003403490	SCV004102811	likely benign	Recombinase activating gene 1 deficiency	2023-11-14	reviewed by expert panel	curation	The c.725A>G, NM_000448.3, variant in RAG1 is a missense variant predicted to cause substitution of Glutamine by Arginine at amino acid 242 (p.Gln242Arg). The filtering allele frequency (the lower threshold of the 95% CI of 477/128678) of the c.725A>G variant in RAG1 is 0.003627 for European (non-Finnish) chromosomes by gnomAD v2.1.1, which is higher than the ClinGen SCID VCEP threshold (0.00195) for BS1, and therefore meets this criterion (BS1). This variant has been detected in at least one individual with Omenn syndrome. The patient is compound heterozygous for the variant R404Q and also carries another variant in RAG1: N766I. There is no information about family segregation. Phase unknown. (PMID: 32311393). No homozygous are found. This patient displays Diagnostic criteria for Omenn syndrome, which reaches 0.5pt, not enough to apply PP4 in any strength (PMID: 32311393, PP4 Not_Met). In summary, this variant meets the criteria to be classified as Likely Benign for autosomal recessive SCID based on the ACMG/AMP criteria applied, BS1, as specified by the ClinGen SCID VCEP (VCEP specifications version 1).
Labcorp Genetics (formerly Invitae), Labcorp	RCV000645698	SCV000767449	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
Illumina Laboratory Services, Illumina	RCV001108566	SCV001265816	benign	Severe combined immunodeficiency, autosomal recessive, T cell-negative, B cell-negative, NK cell-positive	2017-04-27	criteria provided, single submitter	clinical testing	This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). No publications were found based on this search. Allele frequency data from public databases was too high to be consistent with this variant causing disease. Therefore, this variant is classified as benign.
Illumina Laboratory Services, Illumina	RCV001108567	SCV001265817	benign	Histiocytic medullary reticulosis	2017-04-27	criteria provided, single submitter	clinical testing	This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). No publications were found based on this search. Allele frequency data from public databases was too high to be consistent with this variant causing disease. Therefore, this variant is classified as benign.
GeneDx	RCV001546604	SCV001766148	uncertain significance	not provided	2022-11-10	criteria provided, single submitter	clinical testing	Has not been previously published as pathogenic in association with RAG1-related disorder or benign to our knowledge; In silico analysis, which includes protein predictors and evolutionary conservation, supports that this variant does not alter protein structure/function; This variant is associated with the following publications: (PMID: 25976673)
Center for Genomics, Ann and Robert H. Lurie Children's Hospital of Chicago	RCV003224364	SCV003920377	likely benign	Combined immunodeficiency due to partial RAG1 deficiency; Combined immunodeficiency with skin granulomas; Histiocytic medullary reticulosis; Severe combined immunodeficiency, autosomal recessive, T cell-negative, B cell-negative, NK cell-positive	2022-11-09	criteria provided, single submitter	clinical testing	This variant has not been reported in the literature but is present in the Genome Aggregation Database (Highest reported MAF 0.2% [192/68038]; https://gnomad.broadinstitute.org/variant/11-36574029-A-G?dataset=gnomad_r3). This variant is present in ClinVar, with multiple labs classifying this variant as Benign or Likely Benign (Variation ID:536967). This variant amino acid Arginine (Arg) is present in several species including multiple mammals and is not well conserved among evolutionarily distant species; this suggests that this variant may not impact the protein. Additional computational prediction tools do not suggest an impact. In summary, data on this variant suggests that this variant does not cause disease but requires further evidence. Therefore, this variant is classified as likely benign.
Genome Diagnostics Laboratory, University Medical Center Utrecht	RCV001546604	SCV001931303	likely benign	not provided		no assertion criteria provided	clinical testing
Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	RCV001546604	SCV001973087	likely benign	not provided		no assertion criteria provided	clinical testing