TBL1XR1

Chr 3AD

TBL1X/Y related 1

Also known as: C21, DC42, IRA1, MRD41, TBLR1

NCBI Gene: 79718ENSG00000177565UniProt: Q9BZK7OMIM: 608628

This gene is a member of the WD40 repeat-containing gene family and shares sequence similarity with transducin (beta)-like 1X-linked (TBL1X). The protein encoded by this gene is thought to be a component of both nuclear receptor corepressor (N-CoR) and histone deacetylase 3 (HDAC 3) complexes, and is required for transcriptional activation by a variety of transcription factors. Mutations in these gene have been associated with some autism spectrum disorders, and one finding suggests that haploinsufficiency of this gene may be a cause of intellectual disability with dysmorphism. Mutations in this gene as well as recurrent translocations involving this gene have also been observed in some tumors. [provided by RefSeq, Mar 2016]

GeneReviewsOMIMResearchGenerating clinical summary…
MultiplemechanismADLOEUF 0.112 OMIM phenotypes
Clinical Summary— TBL1XR1
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Gene-Disease Validity (ClinGen)
complex neurodevelopmental disorder · ADDefinitive

Definitive — sufficient evidence for diagnostic panels

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Population Constraint (gnomAD)
Highly constrained gene — heterozygous loss-of-function variants are very rare in the population (pLI 1.00). One damaged copy is likely sufficient to cause disease.
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ClinVar Variants
115 unique Pathogenic / Likely Pathogenic· 239 VUS of 708 total submissions
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Clinical Trials
2 active or recruiting trials — potential therapeutic options may be available
Explore recent and relevant literature in Research Assistant →
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GeneReview available — TBL1XR1
Authoritative clinical overview · Recommended first read
Open GeneReview ↗

Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

gnomAD
Dual constrained — LoF & missense intolerant
LoF Constraint?
0.11LOEUF
pLI 1.000
Z-score 4.91
OE 0.00 (0.00–0.11)
Highly constrained

Among the most LoF-intolerant genes (~top 3%)

Missense Constraint?
4.20Z-score
OE missense 0.27 (0.22–0.33)
69 obs / 259.6 exp
Constrained

Highly missense-constrained (top ~0.1%)

Observed / Expected Ratios?
LoF OE?0.00 (0.00–0.11)
0≤0.351.4
Missense OE?0.27 (0.22–0.33)
0≤0.61.4
Synonymous OE?1.05
0≤1.21.6
LoF obs/exp: 0 / 28.1Missense obs/exp: 69 / 259.6Syn Z: -0.38
Curated Mechanism (G2P)Gene2Phenotype (DDG2P) ↗
definitiveTBL1XR1-related intellectual disability with autism spectrum disorderLOFAD
definitiveTBL1XR1-related Pierpont syndromeGOFAD

This gene — mechanism propensity

DN
0.2698th %ile
GOF
0.3491th %ile
LOF
0.83top 5%

This gene has evidence for multiple mechanisms of pathogenicity (loss-of-function and dominant-negative). Both the Badonyi & Marsh prediction and the broader genomic evidence point to loss-of-function as the predominant mechanism. Different variants in this gene may act through different mechanisms — interpret in context of the specific variant.

LOFprediction above median · 1 literature citation · 35% of P/LP variants are LoF · LOEUF 0.11 · ClinGen HI: Sufficient evidence for dosage pathogenicity
DN1 literature citation

Note: In-silico variant effect predictors (SIFT, PolyPhen, REVEL, CADD) may underestimate pathogenicity of missense variants in genes with GOF or DN mechanisms. Consider functional evidence and clinical context.

Literature Evidence

DNA dominant-negative effect of this mutation is strongly suspected, since patients with TBL1XR1 deletion and other variants predicting loss of function do not share the same phenotype.1
LOFOur report supports that haploinsufficiency for TBL1XR1 could be implicated in non-ASD autosomal dominant ID.2

Predictions from Badonyi M, Marsh JA. PLoS ONE. 2024;19(8):e0307312. Mechanism ranking also informed by gnomAD constraint, ClinVar, and ClinGen data.

References

  1. 1.PMID 30365874 ↗
  2. 2.PMID 24891185 ↗

ClinVar Variant Classifications

708 submitted variants in ClinVar

ClinVar

Classification Summary

Pathogenic39
Likely Pathogenic76
VUS239
Likely Benign263
Benign40
Conflicting20
39
Pathogenic
76
Likely Pathogenic
239
VUS
263
Likely Benign
40
Benign
20
Conflicting

Curated Variants Distribution

Classified variants from ClinVar · 5 ACMG categories

ClassificationLoFMissense + InframeNon-codingSynonymousTotal
Pathogenic
22
17
0
0
39
Likely Pathogenic
18
55
3
0
76
VUS
1
211
23
4
239
Likely Benign
0
1
140
122
263
Benign
0
0
39
1
40
Conflicting
—20
Total41284205127677

LoF = frameshift, stop gained/lost, canonical splice · Counts from ClinVar esearch · Updated hourly

View in ClinVar →

32 pathogenic / likely-pathogenic (of 63) ClinVar copy-number / structural variants overlap TBL1XR1 — these span large chromosomal regions, not the gene specifically, and are excluded from the counts above. Explore in CNV tools →

Protein Context — Lollipop Plot

TBL1XR1 · protein map & ClinVar variants

Showing all ClinVar variants across the protein. Search a specific variant to highlight its position.

External Resources

Links to major genomics databases and tools

Franklin by Genoox
AI-powered variant curation and clinical analysis
DECIPHER
Genomic variants and phenotypes in rare disease patients