Evidence Repository
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Variant: NM_000448.3(RAG1):c.2487_2488delinsTT (p.Arg829_Lys830delinsSerTer)

CA1139532300

1034220 (ClinVar)

Gene: RAG1
Condition: recombinase activating gene 1 deficiency
Inheritance Mode: Autosomal recessive inheritance
Link to MONDO
UUID: f8457616-82a4-4ca6-b0fa-f254b1ab98ad
Approved on: 2024-01-17
Published on: 2024-01-17

HGVS expressions

NM_000448.3:c.2487_2488delinsTT
NM_000448.3(RAG1):c.2487_2488delinsTT (p.Arg829_Lys830delinsSerTer)
NC_000011.10:g.36575791_36575792delinsTT
CM000673.2:g.36575791_36575792delinsTT
NC_000011.9:g.36597341_36597342delinsTT
CM000673.1:g.36597341_36597342delinsTT
NC_000011.8:g.36553917_36553918delinsTT
NG_007528.1:g.12779_12780delinsTT
ENST00000299440.6:c.2487_2488delinsTT
ENST00000299440.5:c.2487_2488delinsTT
ENST00000524423.1:n.311_312delinsAA
ENST00000534663.1:c.2487_2488delinsTT
NM_000448.2:c.2487_2488delinsTT
NM_001377277.1:c.2487_2488delinsTT
NM_001377278.1:c.2487_2488delinsTT
NM_001377279.1:c.2487_2488delinsTT
NM_001377280.1:c.2487_2488delinsTT

Pathogenic

Met criteria codes 4
PM2_Supporting PM3 PVS1 PP4
Not Met criteria codes 5
BA1 PM1 BS3 BS1 PS3

Evidence Links 0

Expert Panel

Criteria Specification Information

Criteria Specification: ClinGen Severe Combined Immunodeficiency Disease Expert Panel Specifications to the ACMG/AMP Variant Interpretation Guidelines for RAG1 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_000448.3:c.2487_2488delinsTT (p.Arg829_Lys830delinsSerTer) variant in RAG1 is a nonsense variant that is not expected to result in nonsense-mediated mRNA decay but is predicted to cause a premature stop codon that leads to the truncation of part of the core region (aa 387-1011) critical to protein function (PVS1; PMID 26996199). This variant is absent from gnomAD v2.1.1. (PM2_Supporting). This variant has been detected in four individuals with SCID. Of those individuals, one individual was homozygous for the variant (0.5pt, PMID 25869295, 30307608). One individual was compound heterozygous (p.K621E, VUS by the SCID VCEP, in trans) (0pt, PMID 30307608). One individual was with this variant and a variant Pathogenic according to the SCID VCEP (p.K86VfsX33), but the phase was not confirmed (0.5pt, PMID 32311393). One individual was reported in a ClinVar entry, but the information on the other allele is not available (0pt, Baylor Genetics, SCV001530390.1). TOTAL: 1.0pt, PM3. PMID 25869295: Patient #4 with this variant was diagnosed with SCID (0.5pt) and displayed a T-B-NK+ profile (0.5pt). Total: 1.0 pt, PP4 is met. In summary, this variant meets the criteria to be classified as Pathogenic for SCID. ACMG/AMP criteria applied, as specified by the ClinGen SCID-VCEP: PVS1, PM2_Supporting, PM3, and PP4. (SCID VCEP specifications version 1.0).
Met criteria codes
PM2_Supporting
This variant is absent from gnomAD v2.1.1 (PM2_Supporting).
PM3
This variant has been detected in four individuals with SCID. Of those individuals, one individual was homozygous for the variant (0.5pt, PMID 25869295, 30307608). One individual was compound heterozygous (p.K621E, VUS by the SCID VCEP, in trans) (0pt, PMID 30307608). One individual was with this variant and a variant Pathogenic according to the SCID VCEP (p.K86VfsX33), but the phase was not confirmed (0.5pt, PMID 32311393). One individual was reported in a ClinVar entry, but the information on the other allele is not available (0pt, Baylor Genetics, SCV001530390.1). TOTAL: 1.0pt, PM3.
PVS1
The c.2487_2488delinsTT (p.Arg829_Lys830delinsSerTer) variant in RAG1 is a nonsense variant that may cause a premature stop codon that is predicted to escape nonsense-mediated decay. However, it is predicted to truncate part of the core region (between aa 387-1011) critical to the function of the protein (PMID 26996199).
PP4
PMID 25869295: Patient #4 with this variant was diagnosed with SCID (0.5pt) and displayed a T-B-NK+ profile (0.5pt). Total: 1.0 pt, PP4 is met.
Not Met criteria codes
BA1
No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
PM1
No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
BS3
No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
BS1
No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
PS3
No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
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