Evidence Repository
The ClinGen Evidence Repository is an FDA-recognized human genetic variant database containing expert-curated assertions regarding variants' pathogenicity and supporting evidence summaries. [Disclaimer]
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Variant: NM_000448.3(RAG1):c.527G>T (p.Cys176Phe)

CA5950000

372487 (ClinVar)

Gene: RAG1
Condition: recombinase activating gene 1 deficiency
Inheritance Mode: Autosomal recessive inheritance
Link to MONDO
UUID: 6a48e5bb-2a2d-497c-a1df-c04ae199de7d

HGVS expressions

NM_000448.3:c.527G>T
NM_000448.3(RAG1):c.527G>T (p.Cys176Phe)
NC_000011.10:g.36573831G>T
CM000673.2:g.36573831G>T
NC_000011.9:g.36595381G>T
CM000673.1:g.36595381G>T
NC_000011.8:g.36551957G>T
NG_007528.1:g.10819G>T
ENST00000299440.6:c.527G>T
ENST00000299440.5:c.527G>T
ENST00000534663.1:c.527G>T
NM_000448.2:c.527G>T
NM_001377277.1:c.527G>T
NM_001377278.1:c.527G>T
NM_001377279.1:c.527G>T
NM_001377280.1:c.527G>T

Uncertain Significance

Met criteria codes 3
PP4 PM3 PM2_Supporting
Not Met criteria codes 5
PS3 PS1 PM1 PM5 BS3

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 c.527G>T (NM_000448.3) variant in RAG1 is a missense variant predicted to cause a substitution of Cysteine by Phenylalanine at amino acid 176 (p.Cys176Phe). The filtering allele frequency (the upper threshold of the 95% CI of 3/128742) of the c.527G>T variant in RAG1 is 0.000002930 for European (non-Finnish) chromosomes by gnomAD v2.1.1, which is lower than the ClinGen SCID VCEP threshold (<0.000102) for PM2_Supporting, and therefore meets this criterion (PM2_Supporting). This variant has been detected in at least two individuals with SCID and Leaky SCID who are homozygous for the variant (1 pt, PM3; PMID: 28769923 and 34539671). At least one patient with this variant displayed Diagnostic criteria for Leaky SCID (0.5pts) + SCID gene panel (0.5pts) + T-B-NK+ lymphocyte subset profile (0.5 pts), total 1.5 points, PP4 met (PMID: 34539671). In summary, this variant meets the criteria to be classified as Uncertain significance for autosomal recessive SCID based on the ACMG/AMP criteria applied, PM2_Supporting, PM3, and PP4, as specified by the ClinGen SCID VCEP (VCEP specifications version 1).
Met criteria codes
PP4
At least one patient with this variant displayed Diagnostic criteria for Leaky SCID (0.5pts) + SCID gene panel (0.5pts) + T-B-NK+ lymphocyte subset profile (0.5 pts), total 1.5 points, PP4 met (PMID: 34539671).
PM3
This variant has been detected in at least two individuals with SCID and Leaky SCID, who are homozygous for the variant (1 pt, PM3; PMID: 28769923 and 34539671).
PM2_Supporting
The filtering allele frequency (the upper threshold of the 95% CI of 3/128742) of the c.527G>T variant in RAG1 is 0.000002930 for European (non-Finnish) chromosomes by gnomAD v2.1.1, which is lower than the ClinGen SCID VCEP threshold (<0.000102) for PM2_Supporting, and therefore meets this criterion (PM2_Supporting).
Not Met criteria codes
PS3
No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
PS1
No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
PM1
The missense variant is not located in the hot spot/critical/well-established functional domain established by SCID-VCEP.
PM5
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
Approved on: 2024-01-17
Published on: 2024-01-17
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