TBL1XR1

Chr 3AD

TBL1X/Y related 1

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

NCBI Gene: 79718 ENSG00000177565 UniProt: Q9BZK7

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]

Primary Disease Associations & Inheritance

Intellectual developmental disorder, autosomal dominant 41MIM #616944

Pierpont syndromeMIM #602342

Active trials

Pathogenic / LP

567

ClinVar variants

Pubs (1 yr)

4.2

Missense Z· constrained

0.11

LOEUF· LoF intolerant

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

97 Pathogenic / Likely Pathogenic· 212 VUS of 567 total submissions

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Clinical Trials

2 active or recruiting trials — potential therapeutic options may be available

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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 OE0.00 (0.00–0.11)

0≤0.351.4

Missense OE0.27 (0.22–0.33)

0≤0.61.4

Synonymous OE1.05

0≤1.21.6

LoF obs/exp: 0 / 28.1Missense obs/exp: 69 / 259.6Syn Z: -0.38

LOFDN

Badonyi & Marsh 2024 ↗

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 · 23% of P/LP variants are LoF · LOEUF 0.11

DN1 literature citation

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.PMID:30365874

LOFOur report supports that haploinsufficiency for TBL1XR1 could be implicated in non-ASD autosomal dominant ID.PMID:24891185

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

ClinVar Variant Classifications

567 submitted variants in ClinVar

ClinVar

Classification Summary

Pathogenic35

Likely Pathogenic62

VUS212

Likely Benign209

Benign35

Conflicting14

Pathogenic

Likely Pathogenic

212

VUS

209

Likely Benign

Benign

Conflicting

Curated Variants Distribution

Classified variants from ClinVar · 5 ACMG categories

Classification	LoF	Missense + Inframe	Non-coding	Synonymous	Total
Pathogenic	13	12	10	0	35
Likely Pathogenic	9	40	13	0	62
VUS	1	158	49	4	212
Likely Benign	0	1	112	96	209
Benign	0	0	34	1	35
Conflicting	—				14
Total	23	211	218	101	567

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

View in ClinVar →

TBL1XR1 · protein map & ClinVar variants

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

Gene2Phenotype Curations

TBL1XR1-related intellectual disability with autism spectrum disorder

definitive

ADLoss Of FunctionAbsent Gene Product

Dev. Disorders

G2P ↗

TBL1XR1-related Pierpont syndrome

definitive

ADGain Of FunctionAltered Gene Product Structure

Dev. Disorders

G2P ↗

Gene2Phenotype curations · DECIPHER consortium patient cohort (public variants) · deciphergenomics.org

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

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GeneReview available — TBL1XR1

Authoritative clinical overview · NCBI Bookshelf · Recommended first read

Open GeneReview ↗

Clinical Trials

Active and recruiting trials from ClinicalTrials.gov

ClinicalTrials.gov

Non-Small Cell Lung CancerMedullary Thyroid CancerColon Cancer

A Study of Selpercatinib (LOXO-292) in Participants With Advanced Solid Tumors, RET Fusion-Positive Solid Tumors, and Medullary Thyroid Cancer (LIBRETTO-001)

ACTIVE NOT RECRUITING

NCT03157128Phase PHASE1, PHASE2Eli Lilly and CompanyStarted 2017-05-02

LOXO-292

Medullary Thyroid CancerInfantile MyofibromatosisInfantile Fibrosarcoma

A Study of Oral LOXO-292 (Selpercatinib) in Pediatric Participants With Advanced Solid or Primary Central Nervous System (CNS) Tumors

ACTIVE NOT RECRUITING

NCT03899792Phase PHASE1, PHASE2Eli Lilly and CompanyStarted 2019-06-13

Selpercatinib

Clinical Literature

Landmark / reviewRecent case evidence

Full-Text Mentions

NLP-detected gene mentions in article bodies · via PubTator3