LETM1

Chr 4AR

leucine zipper and EF-hand containing transmembrane protein 1

Also known as: CONDMIM, KHE, Mdm38, SLC55A1

NCBI Gene: 3954 ENSG00000168924 UniProt: O95202 OMIM: 604407

The LETM1 protein localizes to the inner mitochondrial membrane where it maintains mitochondrial tubular morphology and mediates calcium and potassium/proton transport across the membrane. Mutations cause childhood-onset neurodegeneration with multisystem involvement due to mitochondrial dysfunction, inherited in an autosomal recessive pattern. The gene shows high constraint against loss-of-function variants (pLI near 1, LOEUF 0.738), indicating that complete loss of function is likely incompatible with survival.

OMIM ResearchSummary from RefSeq, OMIM, UniProt

This gene encodes a protein that is localized to the inner mitochondrial membrane. The protein functions to maintain the mitochondrial tubular shapes and is required for normal mitochondrial morphology and cellular viability. Mutations in this gene cause Wolf-Hirschhorn syndrome, a complex malformation syndrome caused by the deletion of parts of the distal short arm of chromosome 4. Related pseudogenes have been identified on chromosomes 8, 15 and 19. [provided by RefSeq, Oct 2009]

OMIM ResearchGenerating clinical summary…

MultiplemechanismARLOEUF 0.741 OMIM phenotype

Clinical Summary— LETM1

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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

10 unique Pathogenic / Likely Pathogenic· 162 VUS of 347 total submissions

Explore recent and relevant literature in Research Assistant →

Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

gnomAD

Tolerant — LoF & missense variants common in population

LoF Constraint?

0.74LOEUF

pLI 0.000

Z-score 2.70

OE 0.48 (0.32–0.74)

Tolerant

Typical tolerance to LoF variation

Missense Constraint?

1.58Z-score

OE missense 0.79 (0.72–0.86)

341 obs / 433.4 exp

Tolerant

Mild missense constraint

Observed / Expected Ratios?

LoF OE?0.48 (0.32–0.74)

0≤0.351.4

Missense OE?0.79 (0.72–0.86)

0≤0.61.4

Synonymous OE?1.15

0≤1.21.6

LoF obs/exp: 15 / 31.3Missense obs/exp: 341 / 433.4Syn Z: -1.65

Curated Mechanism (G2P)Gene2Phenotype (DDG2P) ↗

moderateLETM1-related neurodevelopmental disorderOTHERAR

This gene — mechanism propensity

Predictions shown for reference only — model trained on dominant genes, not applicable to AR conditions.

0.75top 25%

GOF

0.6833th %ile

LOF

0.3066th %ile

The Badonyi & Marsh prediction model was trained exclusively on dominant disease genes. Predictions are not reliable for genes with autosomal recessive inheritance and are shown at reduced opacity for reference only.

Predictions from Badonyi M, Marsh JA. PLoS ONE. 2024;19(8):e0307312.

ClinVar Variant Classifications

347 submitted variants in ClinVar

ClinVar

Classification Summary

Pathogenic7

Likely Pathogenic3

VUS162

Likely Benign134

Benign25

Conflicting3

Pathogenic

Likely Pathogenic

162

VUS

134

Likely Benign

Benign

Conflicting

Curated Variants Distribution

Classified variants from ClinVar · 5 ACMG categories

Classification	LoF	Missense + Inframe	Non-coding	Synonymous	Total
Pathogenic	1	5	1	0	7
Likely Pathogenic	2	1	0	0	3
VUS	5	144	10	3	162
Likely Benign	0	10	38	86	134
Benign	0	11	6	8	25
Conflicting	—				3
Total	8	171	55	97	334

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

View in ClinVar →

154 pathogenic / likely-pathogenic (of 166) ClinVar copy-number / structural variants overlap LETM1 — these span large chromosomal regions, not the gene specifically, and are excluded from the counts above. Explore in CNV tools →