TOP1MT

Chr 8

DNA topoisomerase I mitochondrial

NCBI Gene: 116447 ENSG00000184428 UniProt: Q969P6 OMIM: 606387

The encoded mitochondrial DNA topoisomerase relieves supercoiling tension during mitochondrial DNA replication and transcription by transiently cleaving and rejoining DNA strands. Mutations cause infantile-onset spinocerebellar ataxia with mitochondrial encephalomyopathy, inherited in an autosomal recessive pattern. The gene shows moderate constraint against loss-of-function variants (LOEUF 1.68), with affected patients presenting with progressive neurodegeneration involving the cerebellum and skeletal muscle.

OMIM ResearchSummary from RefSeq, UniProt

This gene encodes a mitochondrial DNA topoisomerase that plays a role in the modification of DNA topology. The encoded protein is a type IB topoisomerase and catalyzes the transient breaking and rejoining of DNA to relieve tension and DNA supercoiling generated in the mitochondrial genome during replication and transcription. Alternatively spliced transcript variants encoding multiple isoforms have been observed for this gene. [provided by RefSeq, May 2012]

OMIM ResearchGenerating clinical summary…

LOEUF 1.68

Clinical Summary— TOP1MT

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Population Constraint (gnomAD)

Low constraint (pLI 0.00) — loss-of-function variants are relatively tolerated in the population.

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ClinVar Variants

194 VUS of 336 total submissions

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Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

gnomAD

Tolerant — LoF & missense variants common in population

LoF Constraint?

1.68LOEUF

pLI 0.000

Z-score -1.70

OE 1.31 (1.03–1.68)

Tolerant

Highly tolerant — LoF variants common in population

Missense Constraint?

-0.11Z-score

OE missense 1.02 (0.93–1.10)

393 obs / 386.9 exp

Tolerant

Tolerant to missense variation

Observed / Expected Ratios?

LoF OE?1.31 (1.03–1.68)

0≤0.351.4

Missense OE?1.02 (0.93–1.10)

0≤0.61.4

Synonymous OE?0.99

0≤1.21.6

LoF obs/exp: 45 / 34.3Missense obs/exp: 393 / 386.9Syn Z: 0.13

ClinVar Variant Classifications

336 submitted variants in ClinVar

ClinVar

Classification Summary

VUS194

Likely Benign93

Benign28

Conflicting3

194

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	0	0	0
Likely Pathogenic	0	0	0	0	0
VUS	17	162	9	6	194
Likely Benign	0	12	32	49	93
Benign	0	10	9	9	28
Conflicting	—				3
Total	17	184	50	64	318

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

View in ClinVar →

60 pathogenic / likely-pathogenic (of 72) ClinVar copy-number / structural variants overlap TOP1MT — these span large chromosomal regions, not the gene specifically, and are excluded from the counts above. Explore in CNV tools →