Evidence Repository - Clinical Genome Resources

The ClinGen Evidence Repository is an FDA-recognized human genetic variant database containing expert-curated assertions regarding variants' pathogenicity and supporting evidence summaries. [Disclaimer]

Link to SEPIO compliant JSON-LD document

Variant: NM_000536.4(RAG2):c.217C>T (p.Arg73Cys)

CA214218

36719 (ClinVar)

Gene: RAG2

Condition: recombinase activating gene 2 deficiency

Inheritance Mode: Autosomal recessive inheritance

Link to MONDO

UUID: ed88a6c9-e610-46f2-a97f-e3d4667b446b

HGVS expressions

NM_000536.4:c.217C>T

NM_000536.4(RAG2):c.217C>T (p.Arg73Cys)

NC_000011.10:g.36593952G>A

CM000673.2:g.36593952G>A

NC_000011.9:g.36615502G>A

CM000673.1:g.36615502G>A

NC_000011.8:g.36572078G>A

NG_007573.1:g.9285C>T

NG_033154.1:g.4460G>A

ENST00000311485.8:c.217C>T

ENST00000311485.7:c.217C>T

ENST00000524423.1:n.131+4150C>T

ENST00000529083.1:c.217C>T

ENST00000618712.4:c.217C>T

NM_000536.3:c.217C>T

NM_001243785.1:c.217C>T

NM_001243786.1:c.217C>T

NM_001243785.2:c.217C>T

NM_001243786.2:c.217C>T

Likely Pathogenic

PP4 PM3 PM1_Supporting PM5_Supporting PM2_Supporting

PS1

Evidence Links 0

Expert Panel

Severe Combined Immunodeficiency Disease VCEP

Criteria Specification Information

Criteria Specification: ClinGen Severe Combined Immunodeficiency Disease Expert Panel Specifications to the ACMG/AMP Variant Interpretation Guidelines for RAG2 Version 1.0.0

Criteria Specification Approval History

Criteria Specifications for this VCEP

Evidence submitted by expert panel

Severe Combined Immunodeficiency Disease VCEP

The c.217C>T (NM_000536.4) variant in RAG2 is a missense variant predicted to cause substitution of Arginine by Cysteine at amino acid 73 (p.Arg73Cys). The filtering allele frequency (the upper threshold of the 95% CI of 2/16256) of the c.217C>T variant in RAG2 is 0.00002132 for African/African American chromosomes by gnomAD v2.1.1 (no homozygous reported), which is lower than the ClinGen SCID VCEP threshold (<0.0000588) for PM2_Supporting, and therefore meets this criterion (PM2_Supporting). This variant resides within a region, amino acids 1-383, of RAG2 that is defined as a critical functional domain by the ClinGen SCID VCEP (PMID: 26996199) (PM1_Supporting). PMID: 24481607: Proband compound heterozygous (comp het ( R73C/C178X, Pathogenic according to SCID VCEP specifications, 1 pt, PM3_met). NM_000536.4(RAG2):c.218G>A (p.Arg73His), LP according to SCID VCEP specifications, PM5_Supporting. At least one patient with this variant displayed: Diagnostic criteria for SCID/Leaky SCID/Omenn syndrome met (0.5pt) and T-B-NK+ lymphocyte subset profile (0.5pt), totalizing 1 pt, which is highly specific for SCID (PP4, PMID: 20603253). In summary, this variant is classified as Likely Pathogenic for AR SCID. ACMG/AMP criteria applied, as specified by the ClinGen SCID VCEP: PP4, PM1_Supporting, PM3, PM5_Supporting, and PM2_Supporting. (VCEP specifications version 1).

PP4

At least one patient with this variant displayed: Diagnostic criteria for SCID/Leaky SCID/Omenn syndrome met (0.5pt) and T-B-NK+ lymphocyte subset profile (0.5pt), totalizing 1 pt, which is highly specific for SCID (PP4, PMID: 20603253).

PM3

PMID: 24481607: Proband compound heterozygous (comp het ( R73C/C178X, Pathogenic according to SCID VCEP specifications, 1 pt, PM3_met).

PM1_Supporting

This variant resides within a region, amino acids 1-383, of RAG2 that is defined as a critical functional domain by the ClinGen SCID VCEP (PMID: 26996199) (PM1_Supporting).

PM5_Supporting

NM_000536.4(RAG2):c.218G>A (p.Arg73His), LP according to SCID VCEP specifications, PM5_Supporting.

PM2_Supporting

The filtering allele frequency (the upper threshold of the 95% CI of 2/16256) of the c.217C>T variant in RAG2 is 0.00002132 for African/African American chromosomes by gnomAD v2.1.1 (no homozygous reported), which is lower than the ClinGen SCID VCEP threshold (<0.0000588) for PM2_Supporting, and therefore meets this criterion (PM2_Supporting).

PS1

No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline

Approved on: 2024-01-17

Published on: 2024-01-17

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