LETM1

leucine zipper and EF-hand containing transmembrane protein 1, the group of Solute carrier family 55, LETM mitochondrial cation/proton exchangers|EF-hand domain containing

Basic information

Region (hg38): 4:1811479-1856156

Links

ENSG00000168924 ∙ NCBI:3954 ∙ OMIM:604407 ∙ HGNC:6556 ∙ Uniprot:O95202 ∙ AlphaFold ∙ GenCC ∙ jax ∙ Sfari ∙ GnomAD ∙ Pubmed ∙ ClinVar

Phenotypes

GenCC

Source: genCC

• neurodegeneration, childhood-onset, with multisystem involvement due to mitochondrial dysfunction (Moderate), mode of inheritance: AR
• neurodegeneration, childhood-onset, with multisystem involvement due to mitochondrial dysfunction (Strong), mode of inheritance: AR
• neurodevelopmental disorder (Moderate), mode of inheritance: AR

Clinical Genomic Database

Source: CGD

Condition	Inheritance	Intervention Categories	Intervention/Rationale	Manifestation Categories	References
Childhood-onset neurodegeneration with multisystem involvement due to mitochondrial dysfunction	AR	Audiologic/Otolaryngologic; Cardiovascular	Early recognition and treatment of hearing impairment may improve outcomes, including speech and language development; The condition can involve early-onset cardiomyopathy, and awareness may allow early management	Audiologic/Otolaryngologic; Biochemical; Cardiovascular; Craniofacial; Endocrine; Musculoskeletal; Neurologic; Ophthalmologic	36055214

ClinVar

This is a list of variants' phenotypes submitted to ClinVar and linked to the LETM1 gene.

Variants pathogenicity by type

Statistics on ClinVar variants can assist in determining whether a specific variant type in the LETM1 gene is commonly pathogenic or not.

In the table, we include only reliable ClinVar variants with their consequences to MANE Select, Mane Plus Clinical transcripts, or transcripts with TSL equals 1. Click the count to view the source variants.

Warning: slight differences between displayed counts and the number of variants in ClinVar may occur, primarily due to (1) the application of a different transcript and/or consequence by our variant effect predictor or (2) differences in clinical significance: we classify Benign/Likely benign variants as Likely benign and Pathogenic/Likely pathogenic variants as Likely pathogenic.

Variant type	Pathogenic	Likely pathogenic	VUS	Likely benign	Benign	Sum
synonymous			2	73	7	82
missense		1	101	6	11	119
nonsense			1			1
start loss						0
frameshift		1	2			3
inframe indel			1			1
splice donor/acceptor (+/-2bp)			1			1
splice region			9	5	1	15
non coding				25	5	30
Total	0	2	108	104	23

Variants in LETM1

This is a list of pathogenic ClinVar variants found in the LETM1 region.

You can filter this list by clicking the number of variants in the Variants pathogenicity by type table.

Position	Type	Phenotype	Significance	ClinVar
4-1814424-C-G		LETM1-associated clinical spectrum with predominant nervous system involvement • Neurodegeneration, childhood-onset, with multisystem involvement due to mitochondrial dysfunction • Global developmental delay	Uncertain significance (Aug 01, 2021)
4-1814441-C-T			Uncertain significance (Nov 01, 2022)
4-1814442-G-A			Likely benign (Nov 27, 2024)
4-1814442-G-T			Likely benign (Jul 21, 2022)
4-1814481-C-T			Likely benign (May 15, 2023)
4-1814505-T-C			Likely benign (Aug 17, 2023)
4-1814517-C-T			Likely benign (Jan 05, 2018)
4-1814527-T-C			Uncertain significance (Sep 27, 2022)
4-1814530-C-T		Inborn genetic diseases	Uncertain significance (Feb 27, 2023)
4-1814549-CT-C		LETM1-associated clinical spectrum with predominant nervous system involvement • Neurodegeneration, childhood-onset, with multisystem involvement due to mitochondrial dysfunction	Pathogenic (Oct 25, 2022)
4-1814554-T-C			Benign (Dec 19, 2023)
4-1814576-A-G			Uncertain significance (Dec 26, 2020)
4-1814582-G-C		LETM1-associated clinical spectrum with predominant nervous system involvement • Neurodegeneration, childhood-onset, with multisystem involvement due to mitochondrial dysfunction	Pathogenic (Oct 26, 2022)
4-1814588-A-G			Likely benign (Aug 10, 2022)
4-1815655-G-A			Benign (Jan 22, 2024)
4-1815669-C-T			Uncertain significance (Nov 07, 2022)
4-1815705-C-T			Uncertain significance (Feb 24, 2024)
4-1815739-T-G			Benign (Jan 23, 2024)
4-1815742-G-A			Likely benign (Sep 27, 2022)
4-1815747-T-C			Uncertain significance (Jun 03, 2024)
4-1815760-C-T			Likely benign (Aug 19, 2022)
4-1815768-C-T		Inborn genetic diseases	Uncertain significance (Jan 08, 2024)
4-1815772-G-T			Likely benign (Aug 01, 2024)
4-1815778-C-T			Likely benign (Nov 05, 2024)
4-1815783-C-G		Inborn genetic diseases	Uncertain significance (Sep 29, 2023)

GnomAD

Source: gnomAD

Gene	Type	Bio Type	Transcript	Coding Exons	Length
LETM1	protein_coding	protein_coding	ENST00000302787	14	44769

pLI Probability LOF Intolerant	pRec Probability LOF Recessive	Individuals with no LOFs	Individuals with Homozygous LOFs	Individuals with Heterozygous LOFs	Defined	p
0.00000121	0.998	125682	0	66	125748	0.000262

	Z-Score	Observed	Expected	Observed/Expected	Mutation Rate	Total Possible in Transcript
Missense	1.58	341	433	0.787	0.0000281	4786
Missense in Polyphen		88	145.98	0.60282		1558
Synonymous	-1.65	219	190	1.15	0.0000131	1492
Loss of Function	2.70	15	31.3	0.480	0.00000143	397

LoF frequencies by population

Ethnicity	Sum of pLOFs	p
African & African-American	0.000566	0.000564
Ashkenazi Jewish	0.00139	0.00139
East Asian	0.0000544	0.0000544
Finnish	0.000139	0.000139
European (Non-Finnish)	0.000203	0.000202
Middle Eastern	0.0000544	0.0000544
South Asian	0.000294	0.000294
Other	0.000163	0.000163

dbNSFP

Source: dbNSFP

• Function: FUNCTION: Mitochondrial proton/calcium antiporter that mediates proton-dependent calcium efflux from mitochondrion (PubMed:19797662). Crucial for the maintenance of mitochondrial tubular networks and for the assembly of the supercomplexes of the respiratory chain (PubMed:18628306). Required for the maintenance of the tubular shape and cristae organization (PubMed:18628306). In contrast to SLC8B1/NCLX, does not constitute the major factor for mitochondrial calcium extrusion (PubMed:24898248). {ECO:0000269|PubMed:18628306, ECO:0000269|PubMed:19797662, ECO:0000269|PubMed:24898248}.
• Pathway: Transport of small molecules;Mitochondrial calcium ion transport (Consensus)

Recessive Scores

• pRec: 0.0964

Intolerance Scores

• loftool: 0.0849
• rvis_EVS: 0.54
• rvis_percentile_EVS: 81.09

Haploinsufficiency Scores

• pHI: 0.106
• hipred: Y
• hipred_score: 0.639
• ghis: 0.449

Essentials

• essential_gene_CRISPR: E
• essential_gene_CRISPR2: S
• essential_gene_gene_trap: E
• gene_indispensability_pred: E
• gene_indispensability_score: 0.990

Gene Damage Prediction

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

Mouse Genome Informatics

• Gene name: Letm1
• Phenotype: cellular phenotype; homeostasis/metabolism phenotype; growth/size/body region phenotype; embryo phenotype; nervous system phenotype (the observable morphological and physiological characteristics of the extensive, intricate network of electochemical structures in the body that is comprised of the brain, spinal cord, nerves, ganglia and parts of the receptor organs that are manifested through development and lifespan); mortality/aging (the observable characteristics related to the ability of a mammalian organism to live and age that are manifested throughout development and life span); cardiovascular system phenotype (the observable morphological and physiological characteristics of the mammalian heart, blood vessels, or circulatory system that are manifested through development and lifespan); behavior/neurological phenotype (the observable actions or reactions of mammalian organisms that are manifested through development and lifespan); liver/biliary system phenotype

Gene ontology

• Biological process: mitochondrial calcium ion transmembrane transport;protein hexamerization;cristae formation;protein homooligomerization;mitochondrial calcium ion homeostasis;calcium export from the mitochondrion
• Cellular component: mitochondrion;mitochondrial inner membrane;integral component of membrane
• Molecular function: calcium ion binding;protein binding;calcium:proton antiporter activity;ribosome binding