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
• neurodegeneration, childhood-onset, with multisystem involvement due to mitochondrial dysfunction (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.

• not_provided (231 variants)
• Inborn_genetic_diseases (93 variants)
• LETM1-associated_clinical_spectrum_with_predominant_nervous_system_involvement (10 variants)
• Neurodegeneration,_childhood-onset,_with_multisystem_involvement_due_to_mitochondrial_dysfunction (8 variants)
• not_specified (7 variants)
• 4p_partial_monosomy_syndrome (4 variants)
• Global_developmental_delay (1 variants)
• SRD5A3-congenital_disorder_of_glycosylation (1 variants)
• Ependymoma (1 variants)
• LETM1-related_disorder (1 variants)

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. These statistics are base on transcript: NM_000012318.3. Only rare variants are included in the table.

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.

Effect	Pathogenic	Likely pathogenic	VUS	Likely benign	Benign	Sum
synonymous		1	5	82	6	94
missense	4	1	143	12	9	169
nonsense			1			1
start loss						0
frameshift	1	1	2			4
splice donor/acceptor (+/-2bp)			5			5
Total	5	3	156	94	15

Highest pathogenic variant AF is 0.000006203551

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
		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

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

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