LIPT1

protein-coding

lipoyltransferase 1

Gene summary

The process of transferring lipoic acid to proteins is a two-step process. The first step is the activation of lipoic acid by lipoate-activating enzyme to form lipoyl-AMP. For the second step, the protein encoded by this gene transfers the lipoyl moiety to apoproteins. Alternative splicing results in multiple transcript variants. A related pseudogene has been identified on chromosome 13. Read-through transcription also exists between this gene and the neighboring downstream mitochondrial ribosomal protein L30 (MRPL30) gene. [provided by RefSeq, Mar 2011]

MANE transcript

NM_145199.3

Inheritance

ClinVar variants

P:14U:75B:26

Top phenotype

Lipoyltransferase 1 deficiency

gnomAD constraint

pLI —, LoF o/e 1.07

Max pathogenic AF

—

Genomic locus

chr2:99,154,955-99,163,157

External References & Databases

Ensembl (ENSG00000144182)

Transcript & Mutation Effects

hg38 • Region Span ~8.2 kb

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GenCC Phenotypes & Disease Associations

Curated gene-disease validity assertions and inheritance patterns

Leigh syndromeMODERATE

Inheritance Pattern: AR

Disease ID:MONDO:0009723

Submitter: ClinGen

The relationship between LIPT1 and Leigh syndrome spectrum was evaluated using the ClinGen Clinical Validity Framework as of November 23, 2020. The LIPT1 gene encodes lipoyltransferase which catalyzes the attachment of lipoate to four mitochondrial enzymes (two of which are important for energy metabolism and two of which are needed for amino acid metabolism). Defects in this process result in a disorder of lipoate biosynthesis which impacts mitochondrial energy generation and amino acid metabolism. The LIPT1 gene was first reported in relation to autosomal recessive Leigh syndrome spectrum in 2013 (PMID: 24341803). Evidence supporting this gene-disease relationship includes case-level data and experimental data. This curation included four unique variants identified in two cases from two publications (PMIDs: 24341803, 29681092). No segregation data were available. Loss of function is implicated as the mechanism of disease. This gene-disease association is also supported by the biochemical function, expression, functional alteration in patient cells, rescue in human cells, and animal models (PMIDs: 27977873, 25613900, 24341803, 28803783, 31042466). In summary, there is moderate evidence to support this gene-disease relationship. While more evidence is needed to establish this relationship definitively, no convincing evidence has emerged that contradicts the gene-disease relationship. This classification was approved by the NICHD U24 ClinGen Mitochondrial Disease Gene Curation Expert Panel on November 23, 2020 (SOP Version 7).

lipoyl transferase 1 deficiencySTRONG

Inheritance Pattern: AR

Disease ID:MONDO:0014576

Submitter: Genomics England PanelApp

lipoyl transferase 1 deficiencySTRONG

Inheritance Pattern: AR

Disease ID:MONDO:0014576

Submitter: Labcorp Genetics (formerly Invitae)

lipoyl transferase 1 deficiencySUPPORTIVE

Inheritance Pattern: AR

Disease ID:MONDO:0014576

Submitter: Orphanet

lipoyl transferase 1 deficiencyMODERATE

Inheritance Pattern: AR

Disease ID:MONDO:0014576

Submitter: Ambry Genetics

lipoyl transferase 1 deficiencySTRONG

Inheritance Pattern: AR

Disease ID:MONDO:0014576

Submitter: PanelApp Australia

lipoyl transferase 1 deficiencySTRONG

Inheritance Pattern: AR

Disease ID:MONDO:0014576

Submitter: G2P

Clinical Genomic Database (CGD)

Lipoyltransferase 1 deficiencyAR

Manifestation: Biochemical; Neurologic

Intervention: General

Rationale: Genetic knowledge may be beneficial related to issues such as selection of optimal supportive care, informed medical decision-making, prognostic considerations, and avoidance of unnecessary testing

Refs: 24256811; 24341803

Source: CGD (NHGRI)

ClinVar Associated Diseases & Phenotypes

Reported disease conditions connected to LIPT1 variants in ClinVar

13 Conditions Cataloged

not providedTotal: 74

Inborn genetic diseasesTotal: 43

Lipoyl transferase 1 deficiencyTotal: 13

LIPT1-related disorderTotal: 10

not specifiedTotal: 9

LIPT1-related disordersTotal: 3

See casesTotal: 2

Leigh syndromeTotal: 2

ClinVar Variants & Pathogenicity by Type

Statistics based on transcript NM_145199.3. 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				20 clinvar	1 clinvar	21
missense	1 clinvar	5 clinvar	70 clinvar	3 clinvar	1 clinvar	80
nonsense		3 clinvar	2 clinvar			5
start loss		1 clinvar		1 clinvar		2
frameshift		4 clinvar	3 clinvar			7
splice donor/acceptor (+/-2bp)						0
Total	1	13	75	24	2	115

Highest pathogenic variant AF is 0.0009130365

Loading ClinVar variants...

Transcript Catalog

Annotated transcript isoforms across RefSeq and Ensembl databases

Showing 4 of 58 transcripts

Transcript ID	Source	Protein ID	Coding Exons	MANE Status
NM_145199.3	RefSeq	NP_660200.1	1	MANE Select
ENST00000651691.1	Ensembl	ENSP00000498546.1	1	MANE Select
NM_001204830.2	RefSeq	NP_001191759.1	1	Standard
NM_015929.4	RefSeq	NP_057013.1	1	Standard

Gene Ontology (GO) Annotations & Pathways

Biological processes, molecular functions, cellular components and pathways

Pathways ConsensusPathDB

Lipoic acid metabolism - Homo sapiens (human)
Metabolism of amino acids and derivatives
Metabolism
lipoate salvage
Glyoxylate metabolism and glycine degradation

Biological Process

cellular protein modification process
lipid metabolic process
protein lipoylation
cellular nitrogen compound metabolic process

Molecular Function

transferase activity, transferring acyl groups

Cellular Component

mitochondrion
mitochondrial matrix

gnomAD Constraint

Source: gnomAD

Gene type: protein_coding
Transcript type: protein_coding
Transcript: ENST00000393477
Coding exons: 1
Length: 8203
Individuals with no LoFs: 125468
Homozygous LoFs: 0
Heterozygous LoFs: 274
Defined: 125742
p: 0.00109

	Z-Score	Observed	Expected	Observed/Expected	Mutation Rate	Total Possible
Missense	0.340	178	191	0.931	0.00000895	2480
Missense (PolyPhen)		52	60.578	0.85839		772
Synonymous	0.582	62	68.1	0.910	0.00000312	700
Loss of Function	-0.196	11	10.3	1.07	4.30e-7	151

Population LoF Frequency

Population	CAF	p-value	Status
African	0.00037	0.00037	rare
Latino/Admixed American	0.00026	0.00026	rare
Ashkenazi Jewish	0.0028	0.0028	notable
East Asian	0.00016	0.00016	rare
Finnish	0.00014	0.00014	rare
European (Non-Finnish)	0.0019	0.0019	notable
South Asian	0.00030	0.00029	rare
Other	0.00049	0.00049	rare

dbNSFP Gene Annotations

Source: dbNSFP

Function: FUNCTION: Catalyzes the transfer of the lipoyl group from lipoyl- AMP to the specific lysine residue of lipoyl domains of lipoate- dependent enzymes. {ECO:0000250}.;

Recessive Scores

pRec: 0.182

Intolerance Scores

LoFtool: 0.143
RVIS EVS: -0.27
RVIS percentile EVS: 34.32

Essentials

Essential (CRISPR): E
Essential (CRISPR2): S
Essential (gene trap): N
Indispensability pred.: N
Indispensability score: 0.00158

Gene Damage Prediction

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