rs6519605 — TBX1

rs6519605 — A Chromosome 22q11 Intergenic Variant Near the Immunoglobulin Lambda Locus

The rsid rs6519605 was merged into rs133255 in dbSNP Build 117 (2003) and refers to a common variant on chromosome 22 at GRCh38 position 25,411,342 — a region of the genome densely populated by immunoglobulin lambda (IGL) gene segments¹¹ immunoglobulin lambda (IGL) gene segments
The IGL locus on chromosome 22 contains approximately 70 variable (V), 7 joining (J), and 7 constant (C) gene segments encoding the lambda light chains of antibodies. This SNP was identified in the GeneOps annotation as a chromosome 22q11 variant associated with the same locus region studied for its role in adolescent idiopathic scoliosis (AIS) susceptibility and Eustachian tube/ear infection biology through the related TBX1 variant rs1978060²² rs1978060.

The C allele at this position represents the minor allele (~21.5% globally), with the A allele being the dominant form in all major populations. No genome-wide significant associations have been established for rs133255 (rs6519605) in any disease context as of 2026, and no ClinVar entries exist. The biological interest of this locus is entirely contextual: it lies within the immunoglobulin lambda gene cluster region of 22q11, a chromosomal neighbourhood with profound relevance to adaptive immunity, B-cell development, and — through the broader 22q11.2 locus — thymic development and T-cell output.

The Mechanism

The chromosome 22q11 region spans approximately 18 to 26 megabases and hosts two functionally distinct but immunologically intertwined domains. The proximal segment (~19-21 Mb) contains the 22q11.2 deletion hotspot³³ 22q11.2 deletion hotspot
The ~2.5-Mb deletion causing DiGeorge/22q11.2 deletion syndrome, which includes TBX1 and causes thymic hypoplasia, anchored by TBX1 at position 19.76 Mb. The distal segment (~22-26 Mb) harbours the immunoglobulin lambda (IGL) locus⁴⁴ immunoglobulin lambda (IGL) locus
Contains ~70 Vλ gene segments, 7 Jλ-Cλ cassettes, and surrogate light-chain genes VpreB and λ5 (IGLL1), all critical for B-cell receptor assembly and pre-B cell checkpoint.

rs133255 (rs6519605) sits at 25.41 Mb, downstream of an annotated lncRNA (ENSG00000272942) and within approximately 40 kilobases of IGLL3P, a pseudogene related to the surrogate light chain component λ5. The surrogate light chain is expressed exclusively during pre-B cell development, forming a pre-BCR complex that gates B-cell maturation at the pre-B cell checkpoint⁵⁵ pre-B cell checkpoint
A developmental checkpoint where the pre-B cell receptor (pre-BCR) signals cell survival and proliferation; failure here causes agammaglobulinaemia. Whether the lncRNA or its downstream regulatory elements play a functional role in IGL gene expression or pre-B cell checkpoint regulation is currently unknown.

The functional consequence assigned by Ensembl VEP for this variant is "downstream_gene_variant" with MODIFIER impact — meaning the change is outside annotated exons and has no predicted effect on protein sequence. The variant may influence enhancer activity or lncRNA expression in B-cell progenitor contexts, but this is entirely hypothetical without experimental evidence.

The Evidence

No genome-wide significant (p < 5×10⁻⁸) associations have been reported for rs133255 (rs6519605) in any GWAS as of 2026. No clinical assertions exist in ClinVar. The variant is highly polymorphic (C allele frequency ~21.5%, A allele ~78.5%), suggesting it is not under strong purifying selection and is unlikely to be individually pathogenic.

The primary evidence underpinning this entry is contextual:

Tian et al. 2017⁶⁶ Tian et al. 2017
Genome-wide association and HLA region fine-mapping studies identify susceptibility loci for multiple common infections — Nature Communications performed GWAS of 23 infections in >200,000 Europeans and identified 59 genome-wide significant associations including loci with roles in embryonic development. The 22q11.21 chromosomal region — anchored by TBX1 — was associated with childhood ear infections and myringotomy, suggesting that variation in this chromosomal neighbourhood influences infection susceptibility through developmental programming of Eustachian tube anatomy and mucosal immunity.

Kou et al. 2019⁷⁷ Kou et al. 2019
Genome-wide association study identifies 14 previously unreported susceptibility loci for adolescent idiopathic scoliosis — Nature Communications identified rs1978060 at 22q11.21 as the lead TBX1 cis-eQTL variant for AIS susceptibility. rs6519605 was listed as a related 22q11 variant in the original annotation of rs1978060, reflecting their shared chromosomal neighbourhood even though they lie ~5.6 Mb apart and are not in strong linkage disequilibrium.

Mattei et al. 1991⁸⁸ Mattei et al. 1991
The human pre-B-specific lambda-like cluster — Genomics established that the VpreB and λ5 (IGLL) genes are located on chromosome 22 at 22q11.2-q12.3, precisely the neighbourhood containing rs133255 (rs6519605). These surrogate light chain genes are critical for the pre-B cell checkpoint, making variants in this region candidates for B-cell development studies, though rs133255 has not been specifically studied in this context.

The overall evidence level is emerging (single-locus contextual inference, no direct association studies). Users should treat this as a locus of biological interest rather than a validated risk factor.

Practical Actions

Because rs6519605 (rs133255) has no validated disease associations, specific clinical recommendations based on this variant alone are not warranted. The chromosome 22q11 regional context — proximity to the IGL locus and the broader TBX1/DiGeorge neighbourhood — may be relevant in two scenarios:

First, individuals with recurrent or unusual infections who also carry other 22q11 region variants (particularly rs1978060 GG) may benefit from a broader immunological evaluation, not because of rs6519605 per se, but because the cumulative 22q11 regional burden can reflect subtle variation in thymic and B-cell developmental programming. Second, researchers and clinicians using genomic data should note this variant's merged status: any dataset referencing rs6519605 after 2003 is using the current identifier rs133255.

Interactions

This variant's most plausible biological relationship is with rs1978060 (TBX1, chr22:19.76 Mb), which lies ~5.6 Mb proximal on the same chromosome. The two variants are not in meaningful linkage disequilibrium given the physical distance, but they share the 22q11 chromosomal neighbourhood. The TBX1 locus governs thymic development (T-cell arm) while the IGL locus governs antibody light chain diversity (B-cell arm) — together covering both adaptive immune compartments from a single chromosomal region.

No compound action is proposed for these two variants because (a) they are not in LD, (b) rs6519605 has no validated phenotypic association, and (c) additive or epistatic interactions have not been studied.