Histiocytic medullary reticulosis: genes and variants

Genes linked to Histiocytic medullary reticulosis

• RAG2: V(D)J recombination-activating protein 2

  Together with RAG1, it restricts and activates V(D)J recombination during lymphocyte development so immunoglobulin and T-cell receptor genes can be assembled. Biallelic loss-of-function variants cause severe combined immunodeficiency or hypomorphic immune-dysregulation syndromes.

  14 disease-causing and 36 uncertain variants in RAG2 are linked to Histiocytic medullary reticulosis.

• RAG1: V(D)J recombination-activating protein 1

  It initiates V(D)J recombination by cutting antigen-receptor gene segments, creating the enormous receptor diversity required for adaptive immunity. Biallelic severe loss-of-function variants cause severe combined immunodeficiency, while hypomorphic alleles can cause Omenn syndrome or combined immunodeficiency with autoimmunity.

  11 disease-causing and 32 uncertain variants in RAG1 are linked to Histiocytic medullary reticulosis.

Where Histiocytic medullary reticulosis variants cluster

• RAG2 PHD-type (positions 416–484): 5 of 14 disease-causing changes, 2.7× more than its size predicts.

Known disease-causing variants in Histiocytic medullary reticulosis

Uncertain variants in Histiocytic medullary reticulosis that look disease-causing

Which prediction tools work for Histiocytic medullary reticulosis

How often each tool ranks a disease-causing variant above a harmless one (AUROC × 100).

• REVEL: 99 out of 100 (learned from overlapping clinical labels, so this is optimistic)
• CATVariant: 98 out of 100 (learned from overlapping clinical labels, so this is optimistic)
• SIFT: 98 out of 100
• CADD: 94 out of 100
• PolyPhen-2: 89 out of 100 (learned from overlapping clinical labels, so this is optimistic)
• phyloP: 85 out of 100

Same protein, different disease

• Combined immunodeficiency with skin granulomas is also caused by RAG2 variants; they fall mostly in different places as the Histiocytic medullary reticulosis variants (33 disease-causing).
• Severe combined immunodeficiency, autosomal recessive, T cell-negative, B cell-negative, NK cell-positive is also caused by RAG2 variants; they fall mostly in different places as the Histiocytic medullary reticulosis variants (32 disease-causing).
• Recombinase activating gene 2 deficiency is also caused by RAG2 variants; they fall partly in the same places as the Histiocytic medullary reticulosis variants (25 disease-causing).
• Inborn error of immunity is also caused by RAG2 variants; they fall mostly in different places as the Histiocytic medullary reticulosis variants (10 disease-causing).
• Severe combined immunodeficiency disease is also caused by RAG2 variants; they fall mostly in different places as the Histiocytic medullary reticulosis variants (7 disease-causing).
• Severe combined immunodeficiency, autosomal recessive, T cell-negative, B cell-negative, NK cell-positive is also caused by RAG1 variants; they fall mostly in different places as the Histiocytic medullary reticulosis variants (52 disease-causing).
• Combined immunodeficiency with skin granulomas is also caused by RAG1 variants; they fall mostly in different places as the Histiocytic medullary reticulosis variants (49 disease-causing).
• Combined immunodeficiency due to partial RAG1 deficiency is also caused by RAG1 variants; they fall mostly in different places as the Histiocytic medullary reticulosis variants (13 disease-causing).
• Severe combined immunodeficiency disease is also caused by RAG1 variants; they fall mostly in different places as the Histiocytic medullary reticulosis variants (8 disease-causing).
• Recombinase activating gene 1 deficiency is also caused by RAG1 variants; they fall mostly in different places as the Histiocytic medullary reticulosis variants (8 disease-causing).

Diseases related to Histiocytic medullary reticulosis

• Severe combined immunodeficiency, autosomal recessive, T cell-negative, B cell-negative, NK cell-positive, also linked to RAG1 and RAG2
• Combined immunodeficiency with skin granulomas, also linked to RAG1 and RAG2
• Severe combined immunodeficiency disease, also linked to RAG1 and RAG2
• Recombinase activating gene 2 deficiency, also linked to RAG2
• Inherited Immunodeficiency Diseases, also linked to RAG1
• Combined immunodeficiency due to partial RAG1 deficiency, also linked to RAG1
• Inborn error of immunity, also linked to RAG2
• Recombinase activating gene 1 deficiency, also linked to RAG1
• Common variable immunodeficiency, also linked to RAG2

Frequently asked questions

Which genes are linked to Histiocytic medullary reticulosis?

In CATVariant, Histiocytic medullary reticulosis is linked to 2 analyzed proteins: RAG2 (V(D)J recombination-activating protein 2) and RAG1 (V(D)J recombination-activating protein 1).

How many genetic variants are linked to Histiocytic medullary reticulosis?

123 variants: 25 are classified as disease-causing (pathogenic or likely pathogenic) in ClinVar and 68 are of uncertain significance or have conflicting reports.

Which uncertain variants in Histiocytic medullary reticulosis look disease-causing?

2 uncertain variants reach the likely-pathogenic range of the ACMG/AMP points scale on computable evidence, for example RAG2 A456D and RAG2 G95R. These are leads for expert review, not diagnoses.

Which variant effect predictor works best for Histiocytic medullary reticulosis?

Among tools not trained on clinical labels, SIFT separates this disease's known disease-causing variants from harmless ones best (AUROC 0.98, based on 25 disease-causing and 27 harmless variants).

About this data

Variant–disease links come from ClinVar, Open Targets and UniProt, pooled from the latest public CATVariant analysis of each human protein. Evidence scores use the ACMG/AMP Bayesian points scale with computable criteria only (position among known disease variants, rarity in gnomAD, calibrated predictors, deep mutational scanning); there is no family or patient data, so they prioritise variants for expert review and never classify them.

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