Submissions for variant NM_000536.4(RAG2):c.909G>T (p.Glu303Asp)

gnomAD frequency: 0.00012  dbSNP: rs141025671

Total submissions: 7

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
ClinGen Severe Combined Immunodeficiency Variant Curation Expert Panel, ClinGen	RCV003991472	SCV004809148	uncertain significance	Recombinase activating gene 2 deficiency	2024-04-01	reviewed by expert panel	curation	The c.909G>T (NM_000536.4) variant in RAG2 is a missense variant predicted to cause the substitution of Glutamic Acid by Aspartic Acid at amino acid 303 (p.Glu303Asp). The Popmax Filtering Allele Frequency (95% confidence) is 0.0001834 in gnomAD v.4 based on the African/African American population, 14/75040 alleles. PM2_Supporting (<0.0000588), BS1 (>0.00195), and BA1 (>0.00872) are not met. No homozygous has been described in gnomAD v.4, and BS2 is not met. This variant is located in the core domain, amino acids 1-383 of RAG2, which is defined as a critical functional domain by the ClinGen SCID VCEP (PMID: 26996199); PM1_Supporting. To our knowledge, this variant has not been reported in the literature in individuals affected with RAG2/SCID-related conditions or in functional studies. In summary, this variant meets the criteria to be classified as a variant of uncertain significance for autosomal recessive recombinase activating gene 2 deficiency based on the ACMG/AMP criteria applied, as specified by the ClinGen SCID VCEP. Criteria applied: PM1_Supporting (VCEP specifications version 1.0).
Illumina Laboratory Services, Illumina	RCV000319939	SCV000371788	uncertain significance	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, this variant could not be ruled out of causing disease and therefore its association with disease required further investigation. A literature search was performed for the gene, cDNA change, and amino acid change (if applicable). No publications were found based on this search. This variant was therefore classified as a variant of unknown significance for this disease.
Illumina Laboratory Services, Illumina	RCV000372164	SCV000371789	uncertain significance	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, this variant could not be ruled out of causing disease and therefore its association with disease required further investigation. A literature search was performed for the gene, cDNA change, and amino acid change (if applicable). No publications were found based on this search. This variant was therefore classified as a variant of unknown significance for this disease.
Center for Genomics, Ann and Robert H. Lurie Children's Hospital of Chicago	RCV000768066	SCV000898928	uncertain significance	Combined immunodeficiency with skin granulomas; Histiocytic medullary reticulosis; Severe combined immunodeficiency, autosomal recessive, T cell-negative, B cell-negative, NK cell-positive	2021-03-30	criteria provided, single submitter	clinical testing	RAG2 NM_000536.3 exon 2 p.Glu303Asp (c.909G>T): This variant has not been reported in the literature but is present in 0.1% (11/10360) of Ashkenazi Jewish alleles in the Genome Aggregation Database (http://gnomad.broadinstitute.org/variant/11-36614810-C-A). This variant is present in ClinVar (Variation ID:304553). Evolutionary conservation and computational predictive tools for this variant are unclear; however, this variant is present in 3 species of fish. In summary, data on this variant is insufficient for disease classification. Therefore, the clinical significance of this variant is uncertain.
Labcorp Genetics (formerly Invitae), Labcorp	RCV000808347	SCV000948454	likely benign	Combined immunodeficiency with skin granulomas; Severe combined immunodeficiency, autosomal recessive, T cell-negative, B cell-negative, NK cell-positive	2024-01-28	criteria provided, single submitter	clinical testing
Breakthrough Genomics, Breakthrough Genomics	RCV004693035	SCV005191253	uncertain significance	not provided		criteria provided, single submitter	not provided
Natera, Inc.	RCV000319939	SCV001457490	uncertain significance	Histiocytic medullary reticulosis	2020-04-13	no assertion criteria provided	clinical testing