Submissions for variant NM_000536.4(RAG2):c.367C>T (p.Arg123Cys)

gnomAD frequency: 0.00016  dbSNP: rs147319483

Total submissions: 8

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Labcorp Genetics (formerly Invitae), Labcorp	RCV000874937	SCV001017184	likely benign	Combined immunodeficiency with skin granulomas; Severe combined immunodeficiency, autosomal recessive, T cell-negative, B cell-negative, NK cell-positive	2025-01-29	criteria provided, single submitter	clinical testing
Illumina Laboratory Services, Illumina	RCV001104352	SCV001261209	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.
Illumina Laboratory Services, Illumina	RCV001104353	SCV001261210	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.
Baylor Genetics	RCV001331313	SCV001523330	uncertain significance	Combined immunodeficiency with skin granulomas	2019-02-06	criteria provided, single submitter	clinical testing	This variant was determined to be of uncertain significance according to ACMG Guidelines, 2015 [PMID:25741868].
Genome-Nilou Lab	RCV001104352	SCV001652723	uncertain significance	Severe combined immunodeficiency, autosomal recessive, T cell-negative, B cell-negative, NK cell-positive	2021-05-18	criteria provided, single submitter	clinical testing
Genome-Nilou Lab	RCV001331313	SCV001806137	uncertain significance	Combined immunodeficiency with skin granulomas	2021-07-22	criteria provided, single submitter	clinical testing
Genome-Nilou Lab	RCV001104353	SCV001806138	uncertain significance	Histiocytic medullary reticulosis	2021-07-22	criteria provided, single submitter	clinical testing
Center for Genomics, Ann and Robert H. Lurie Children's Hospital of Chicago	RCV003224483	SCV003920378	uncertain significance	Combined immunodeficiency with skin granulomas; Histiocytic medullary reticulosis; Severe combined immunodeficiency, autosomal recessive, T cell-negative, B cell-negative, NK cell-positive	2023-01-18	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 0.03% [21/68030]; https://gnomad.broadinstitute.org/variant/11-36593802-G-A?dataset=gnomad_r3). This variant is present in ClinVar (Variation ID: 704774). This variant amino acid Cysteine (Cys) 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 is insufficient for disease classification. Therefore, the clinical significance of this variant is uncertain.