TBL1X

Chr XX-linked

transducin beta like 1 X-linked

Also known as: CHNG8, EBI, SMAP55, TBL1

NCBI Gene: 6907 ENSG00000101849 UniProt: O60907 OMIM: 300196

The protein functions as an F-box-like protein that recruits the ubiquitin/proteasome complex to nuclear receptor-regulated transcription units and plays an essential role in transcription activation by mediating degradation of repressor complexes. Mutations cause X-linked congenital nongoitrous hypothyroidism. This gene is highly constrained against loss-of-function variants, indicating that such variants are likely to be pathogenic.

OMIM ResearchSummary from RefSeq, OMIM, UniProt

The protein encoded by this gene has sequence similarity with members of the WD40 repeat-containing protein family. The WD40 group is a large family of proteins, which appear to have a regulatory function. It is believed that the WD40 repeats mediate protein-protein interactions and members of the family are involved in signal transduction, RNA processing, gene regulation, vesicular trafficking, cytoskeletal assembly and may play a role in the control of cytotypic differentiation. This encoded protein is found as a subunit in corepressor SMRT (silencing mediator for retinoid and thyroid receptors) complex along with histone deacetylase 3 protein. This gene is located adjacent to the ocular albinism gene and it is thought to be involved in the pathogenesis of the ocular albinism with late-onset sensorineural deafness phenotype. Four transcript variants encoding two different isoforms have been found for this gene. This gene is highly similar to the Y chromosome TBL1Y gene. [provided by RefSeq, Nov 2008]

OMIM ResearchGenerating clinical summary…

LOFmechanismX-linkedLOEUF 0.311 OMIM phenotype

Clinical Summary— TBL1X

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Population Constraint (gnomAD)

Highly constrained gene — heterozygous loss-of-function variants are very rare in the population (pLI 0.98). One damaged copy is likely sufficient to cause disease.

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ClinVar Variants

3 unique Pathogenic / Likely Pathogenic· 86 VUS of 222 total submissions

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Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

gnomAD

LoF intolerant — likely haploinsufficient

LoF Constraint?

0.31LOEUF

pLI 0.979

Z-score 4.09

OE 0.12 (0.05–0.31)

Highly constrained

Highly LoF-intolerant (top ~10% of genes)

Missense Constraint?

2.48Z-score

OE missense 0.56 (0.48–0.64)

138 obs / 247.8 exp

Mild constraint

Moderately missense-constrained (top ~2.5%)

Observed / Expected Ratios?

LoF OE?0.12 (0.05–0.31)

0≤0.351.4

Missense OE?0.56 (0.48–0.64)

0≤0.61.4

Synonymous OE?1.04

0≤1.21.6

LoF obs/exp: 3 / 25.1Missense obs/exp: 138 / 247.8Syn Z: -0.34

This gene — mechanism propensity

0.3991th %ile

GOF

0.4085th %ile

LOF

0.75top 10%

The highest-scoring mechanism for this gene is loss-of-function (haploinsufficiency).

LOFprediction above median · LOEUF 0.31

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

222 submitted variants in ClinVar

ClinVar

Classification Summary

Pathogenic2

Likely Pathogenic1

VUS86

Likely Benign8

Benign16

Conflicting1

Pathogenic

Likely Pathogenic

VUS

Likely Benign

Benign

Conflicting

Curated Variants Distribution

Classified variants from ClinVar · 5 ACMG categories

Classification	LoF	Missense + Inframe	Non-coding	Synonymous	Total
Pathogenic	0	0	2	0	2
Likely Pathogenic	1	0	0	0	1
VUS	1	77	7	1	86
Likely Benign	0	2	0	6	8
Benign	0	1	12	3	16
Conflicting	—				1
Total	2	80	21	10	114

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

View in ClinVar →

85 pathogenic / likely-pathogenic (of 93) ClinVar copy-number / structural variants overlap TBL1X — these span large chromosomal regions, not the gene specifically, and are excluded from the counts above. Explore in CNV tools →