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.955G>T (p.Gly319Ter)

CA220579698

500475 (ClinVar)

Gene: RAG2

Condition: recombinase activating gene 2 deficiency

Inheritance Mode: Autosomal recessive inheritance

Link to MONDO

UUID: 51af7bdf-04dc-48ca-b682-c0fbebfaae5f

Approved on: 2024-01-17

Published on: 2024-01-17

HGVS expressions

NM_000536.4:c.955G>T

NM_000536.4(RAG2):c.955G>T (p.Gly319Ter)

NC_000011.10:g.36593214C>A

CM000673.2:g.36593214C>A

NC_000011.9:g.36614764C>A

CM000673.1:g.36614764C>A

NC_000011.8:g.36571340C>A

NG_007573.1:g.10023G>T

NG_033154.1:g.3722C>A

ENST00000311485.8:c.955G>T

ENST00000311485.7:c.955G>T

ENST00000524423.1:n.131+4888G>T

ENST00000618712.4:c.955G>T

NM_000536.3:c.955G>T

NM_001243785.1:c.955G>T

NM_001243786.1:c.955G>T

NM_001243785.2:c.955G>T

NM_001243786.2:c.955G>T

Likely Pathogenic

PVS1 PM2_Supporting

PS4

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 NM_000536.4:c.955G>T variant in RAG2 is a nonsense variant predicted to result in a truncated protein (p.Gly319*). Although this variant is expected to escape nonsense-mediated decay (NMD), it would be expected to disrupt approximately 40% of the RAG2 protein. In addition, this variant would be expected to disrupt/remove the entire PHD domain (amino acids 414-487), which is defined as a mutational hotspot/critical functional domain by the ClinGen SCID VCEP (PMID: 15964836). PVS1 met. This variant is absent from gnomAD v2.1.1 (PM2_Supporting). To our knowledge, the variant has not been identified in the literature in patients/case reports or functional studies. In summary, this variant meets the criteria to be classified as Likely Pathogenic for autosomal recessive SCID based on the ACMG/AMP criteria applied, as specified by the ClinGen SCID VCEP: PM2 and PVS1 (VCEP specifications version 1).

PVS1

This truncation Gly319* is not expected to undergo nonsense-mediated decay (NMD) but would be expected to remove around 40% of the total RAG2 protein (would remove 209/527 amino acids). In addition, it would remove the entire PHD domain (amino acids 414-487), which is defined by the SCID VCEP as a region critical to RAG2 protein function (PMID: 15964836). Therefore PVS1 is met.

PM2_Supporting

This variant is absent from gnomAD v2.1.1 (PM2_Supporting).

PS4

To our knowledge, the variant has not been identified in the literature in SCID patients.

The information on this website is not intended for direct diagnostic use or medical decision-making without review by a genetics professional. Individuals should not change their health behavior solely on the basis of information contained on this website. If you have questions about the information contained on this website, please see a health care professional.