TMLHE

Chr XXLR

trimethyllysine hydroxylase, epsilon

Also known as: AUTSX6, BBOX2, TMLD, TMLH, TMLHED, XAP130

NCBI Gene: 55217ENSG00000185973UniProt: Q9NVH6

This gene encodes the protein trimethyllysine dioxygenase which is the first enzyme in the carnitine biosynthesis pathway. Carnitine play an essential role in the transport of activated fatty acids across the inner mitochondrial membrane. The encoded protein converts trimethyllysine into hydroxytrimethyllysine. A pseudogene of this gene is found on chromosome X. Alternate splicing results in multiple transcript variants.[provided by RefSeq, May 2010]

Primary Disease Associations & Inheritance

{Autism, susceptibility to, X-linked 6}MIM #300872
XLR
UniProtAutism, X-linked 6
227
ClinVar variants
132
Pathogenic / LP
0.00
pLI score
0
Active trials
Clinical Summary— TMLHE
🧬
Gene-Disease Validity (ClinGen)
autism spectrum disorder · XLDisputed

Disputed — evidence questions this relationship

⚡
Population Constraint (gnomAD)
Low constraint (pLI 0.00) — loss-of-function variants are relatively tolerated in the population.
📋
ClinVar Variants
132 Pathogenic / Likely Pathogenic· 76 VUS of 227 total submissions

Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

gnomAD
Tolerant — LoF & missense variants common in population
LoF Constraint?LOEUF (Loss-of-function Observed/Expected Upper bound Fraction) is the upper bound of the 90% CI for LoF OE — the preferred gnomAD v4 metric. Lower = more intolerant to LoF. LOEUF < 0.35 = highly constrained.
1.18LOEUF
pLI 0.000
Z-score 1.13
OE 0.65 (0.38–1.18)
Tolerant

Highly tolerant — LoF variants common in population

Missense Constraint?Missense Z-score: standard deviations fewer missense variants observed vs. expected. Z > 3.09 (p < 0.001) = gene does not tolerate missense variation. OE missense < 0.6 is also considered constrained.
0.64Z-score
OE missense 0.84 (0.72–0.99)
112 obs / 132.7 exp
Tolerant

Mild missense constraint

Observed / Expected Ratios?Shaded band = 90% confidence interval. Vertical tick = point estimate. Grey threshold line = gnomAD constraint cutoff for that variant class.
LoF OE?Ratio of observed to expected LoF variants. Upper CI bound (LOEUF) ≤ 0.35 = strong LoF constraint signal.0.65 (0.38–1.18)
0≤0.351.4
Missense OE?Ratio of observed to expected missense variants. OE ≤ 0.6 = fewer missense variants than expected by chance.0.84 (0.72–0.99)
0≤0.61.4
Synonymous OE?Control metric — synonymous variants are largely neutral and expected near OE = 1.0. Significant deviation may indicate annotation issues.1.06
0≤1.21.6
LoF obs/exp: 8 / 12.3Missense obs/exp: 112 / 132.7Syn Z: -0.35

ClinVar Variant Classifications

227 submitted variants in ClinVar

ClinVar

Classification Summary

Pathogenic124
Likely Pathogenic8
VUS76
Likely Benign16
Benign2
Conflicting1
124
Pathogenic
8
Likely Pathogenic
76
VUS
16
Likely Benign
2
Benign
1
Conflicting

Curated Variants Distribution

Classified variants from ClinVar · 5 ACMG categories

ClassificationLoFMissense + InframeNon-codingSynonymousTotal
Pathogenic
1
0
123
0
124
Likely Pathogenic
1
1
6
0
8
VUS
3
47
25
1
76
Likely Benign
0
5
5
6
16
Benign
0
0
1
1
2
Conflicting
—1
Total5531608227

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

View in ClinVar →

Protein Context — Lollipop Plot

TMLHE · protein map & ClinVar variants

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

OMIM — Genotype-Phenotype Relationships

1 OMIM entry

OMIM

{Autism, susceptibility to, X-linked 6}

MIM #300872

Molecular basis of disorder known

X-linked recessive
Clinical Literature
Landmark / reviewRecent case evidence
Key Publications
Landmark & review papers · by relevance
PubMed
Whole-genome sequencing analysis of Japanese autism spectrum disorder trios.
Furukawa S et al.·Psychiatry Clin Neurosci
2025
Genomic alterations in normal breast tissues preceding breast cancer diagnosis.
Dai J et al.·Breast Cancer Res
2025
Brain carnitine deficiency causes nonsyndromic autism with an extreme male bias: A hypothesis.
Beaudet AL·Bioessays
2017Review
Complex recombination with deletion in the F8 and duplication in the TMLHE mediated by int22h copies during early embryogenesis.
Chen C et al.·Thromb Haemost
2017Case report
Use of array CGH to detect exonic copy number variants throughout the genome in autism families detects a novel deletion in TMLHE.
Celestino-Soper PB et al.·Hum Mol Genet
2011
High Functioning Autism with Missense Mutations in Synaptotagmin-Like Protein 4 (SYTL4) and Transmembrane Protein 187 (TMEM187) Genes: SYTL4- Protein Modeling, Protein-Protein Interaction, Expression Profiling and MicroRNA Studies.
Rafi SK et al.·Int J Mol Sci
2019Functional
Refinement of the X-linked nonsyndromic high-grade myopia locus MYP1 on Xq28 and exclusion of 13 known positional candidate genes by direct sequencing.
Ratnamala U et al.·Invest Ophthalmol Vis Sci
2011
Top 10 resultsSearch PubMed ↗
Recent Gene-Specific Literature
Gene in title · MEDLINE · newest first
Europe PMC
Top 5 resultsSearch Europe PMC ↗

Clinical Trials

Active and recruiting trials from ClinicalTrials.gov

ClinicalTrials.gov

No active trials found for this gene.

Search ClinicalTrials.gov →

External Resources

Links to major genomics databases and tools