TMLHE

protein-coding

trimethyllysine hydroxylase, epsilon

Gene summary

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]

MANE transcript

NM_018196.4

Inheritance

XL, AD

ClinVar variants

P:4U:133B:13

Top phenotype

Epsilon-trimethyllysine hydroxylase deficiency

gnomAD constraint

pLI —, LoF o/e 0.65

Max pathogenic AF

—

Genomic locus

chrX:155,489,011-155,719,098

External References & Databases

Ensembl (ENSG00000185973)

Transcript & Mutation Effects

hg38 • Region Span ~230.1 kb

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GenCC Phenotypes & Disease Associations

Curated gene-disease validity assertions and inheritance patterns

autism spectrum disorderNO_KNOWN

Inheritance Pattern: XL

Disease ID:MONDO:0005258

Submitter: ClinGen

The X-linked *TMLHE* gene encodes trimethyllysine dioxygenase, the first enzyme in the carnitine biosynthesis pathway. Celestino-Soper et al. (2011, PMID: 21865298) identified a deletion of exon 2 of *TMLHE* resulting in enzyme deficiency in a male with autism spectrum disorder (ASD). Subsequently, Celestino-Soper et al. (2012, PMID: 22566635) reported a total of 16 male ASD probands, 6 affected male siblings, and 24 healthy adult males with deletions of exon 2, indicating that this is a relatively common variant. The frequency of TMLHE deficiency in probands from simplex autism families (9 in 2,904 or 1 in 323) was not increased compared to control males (24 in 8,787 or 1 in 366). In agreement with these findings, *TMLHE* is not constrained for truncating variants (pLI = 0 in gnomAD v2.1.1). Therefore, these deletions were not scored. Three sequence variants resulting in TMLHE deficiency (nonsense, frameshift, and missense) have been reported in males with ASD (PMID: 23092983, 25943046). These variants were also not scored given the lack of evidence regarding their implication in ASD. No experimental evidence was applicable to the relationship between *TMLHE* and autism. Reduced Tmlhe expression caused diminished neural stem cell pools in the mouse embryonic neocortex and carnitine supplementation rescued this phenotype (PMID: 26832401). In the absence of human genetic evidence linking *TMLHE* to autism, this experimental evidence was not scored. In summary, the genetic evidence reported thus far does not provide convincing evidence to support a role for *TMLHE* in ASD, so this gene-disease relationship was classified as disputed. This classification was approved by the ClinGen Intellectual Disability/Autism GCEP on the meeting date March 2, 2021 (SOP Version 8).

epsilon-trimethyllysine hydroxylase deficiencyLIMITED

Inheritance Pattern: XL

Disease ID:MONDO:0010469

Submitter: PanelApp Australia

epsilon-trimethyllysine hydroxylase deficiencyLIMITED

Inheritance Pattern: Unknown

Disease ID:MONDO:0010469

Submitter: Labcorp Genetics (formerly Invitae)

Clinical Genomic Database (CGD)

Epsilon-trimethyllysine hydroxylase deficiencyAD

Manifestation: Biochemical; Neurologic

Intervention: Biochemical

Rationale: The condition may be associated with autism, and carnitine supplementation has been reported as beneficial related to developmental milestones

Refs: 21865298; 22566635; 25943046

Source: CGD (NHGRI)

ClinVar Associated Diseases & Phenotypes

Reported disease conditions connected to TMLHE variants in ClinVar

8 Conditions Cataloged

not specifiedTotal: 53

not providedTotal: 27

Epsilon-trimethyllysine hydroxylase deficiencyTotal: 18

TMLHE-related disorderTotal: 7

Isolated cerebellar hypoplasia/agenesisTotal: 1

Corpus callosum, agenesis ofTotal: 1

Cerebellar vermis hypoplasiaTotal: 1

Intellectual disabilityTotal: 1

ClinVar Variants & Pathogenicity by Type

Statistics based on transcript NM_018196.4. Only rare variants are included.

We include only reliable ClinVar variants with their consequences to MANE Select, MANE Plus Clinical transcripts, or transcripts with TSL equal to 1. Click a count to filter the variants table below.

Slight differences between displayed counts and ClinVar may occur due to a different transcript/consequence chosen by our variant effect predictor, or because we classify Benign/Likely benign as Likely benign and Pathogenic/Likely pathogenic as Likely pathogenic.

Effect	PathogenicP	Likely pathogenicLP	VUS	Likely benignLB	BenignB	Sum
synonymous			16 clinvar	7 clinvar	1 clinvar	24
missense			93 clinvar	5 clinvar		98
nonsense		1 clinvar	9 clinvar			10
start loss						0
frameshift	1 clinvar		2 clinvar			3
splice donor/acceptor (+/-2bp)		2 clinvar	13 clinvar			15
Total	1	3	133	12	1	150

Highest pathogenic variant AF is 0.0000027943577

Loading ClinVar variants...

Transcript Catalog

Annotated transcript isoforms across RefSeq and Ensembl databases

Showing 4 of 49 transcripts

Transcript ID	Source	Protein ID	Coding Exons	MANE Status
NM_018196.4	RefSeq	NP_060666.1	7	MANE Select
ENST00000334398.8	Ensembl	ENSP00000335261.3	7	MANE Select
NM_001184797.2	RefSeq	NP_001171726.1	6	Standard
ENST00000369439.4	Ensembl	ENSP00000358447.4	6	Standard

Gene Ontology (GO) Annotations & Pathways

Biological processes, molecular functions, cellular components and pathways

Pathways ConsensusPathDB

Lysine degradation - Homo sapiens (human)
Carnitine Synthesis
Branched-chain amino acid catabolism
Metabolism of amino acids and derivatives
Metabolism

Biological Process

carnitine biosynthetic process
oxidation-reduction process

Molecular Function

iron ion binding
protein binding
oxidoreductase activity, acting on single donors with incorporation of molecular oxygen, incorporation of two atoms of oxygen
trimethyllysine dioxygenase activity

Cellular Component

mitochondrion
mitochondrial matrix

gnomAD Constraint

Source: gnomAD

Gene type: protein_coding
Transcript type: protein_coding
Transcript: ENST00000334398
Coding exons: 7
Length: 179830
Individuals with no LoFs: 125709
Homozygous LoFs: 12
Heterozygous LoFs: 16
Defined: 125737
p: 0.000111

	Z-Score	Observed	Expected	Observed/Expected	Mutation Rate	Total Possible
Missense	0.637	112	133	0.844	0.00000987	2753
Missense (PolyPhen)		37	47.984	0.77109		933
Synonymous	-0.348	54	50.8	1.06	0.00000380	786
Loss of Function	1.13	8	12.3	0.652	8.29e-7	250

Population LoF Frequency

Population	CAF	p-value	Status
African	0.000078	0.000062	rare
Latino/Admixed American	0.00035	0.00026	rare
Ashkenazi Jewish	0.00013	0.000099	rare
East Asian	0	0.0	absent
Finnish	0.000063	0.000046	rare
European (Non-Finnish)	0.00010	0.000070	rare
South Asian	0.00045	0.00026	rare
Other	0	0.0	absent

dbNSFP Gene Annotations

Source: dbNSFP

Function: FUNCTION: Converts trimethyllysine (TML) into hydroxytrimethyllysine (HTML) (PubMed:11431483, PubMed:23092983). {ECO:0000269|PubMed:11431483, ECO:0000269|PubMed:23092983}.;

Recessive Scores

pRec: 0.113

Intolerance Scores

LoFtool: 0.228
RVIS EVS: -0.14
RVIS percentile EVS: 43.29

Essentials

Essential (CRISPR): N
Essential (CRISPR2): N
Essential (gene trap): N
Indispensability pred.: E
Indispensability score: 0.879

Gene Damage Prediction

	All	Recessive	Dominant
Mendelian	Medium	Medium	Medium
Primary Immunodeficiency	Medium	Medium	Medium
Cancer	Medium	Medium	Medium