LETM1

protein-coding

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

Gene summary

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]

MANE transcript

NM_012318.3

Inheritance

ClinVar variants

P:9U:160B:116

Top phenotype

Childhood-onset neurodegeneration with multisystem involvement due to mitochondrial dysfunction

gnomAD constraint

pLI —, LoF o/e 0.48

Max pathogenic AF

—

Genomic locus

chr4:1,811,479-1,856,156

External References & Databases

Ensembl (ENSG00000168924)

Transcript & Mutation Effects

hg38 • Region Span ~44.7 kb

Loading mutation effect viewer...

GenCC Phenotypes & Disease Associations

Curated gene-disease validity assertions and inheritance patterns

neurodegeneration, childhood-onset, with multisystem involvement due to mitochondrial dysfunctionSTRONG

Inheritance Pattern: AR

Disease ID:MONDO:0859304

Submitter: PanelApp Australia

neurodegeneration, childhood-onset, with multisystem involvement due to mitochondrial dysfunctionMODERATE

Inheritance Pattern: AR

Disease ID:MONDO:0859304

Submitter: Ambry Genetics

neurodegeneration, childhood-onset, with multisystem involvement due to mitochondrial dysfunctionMODERATE

Inheritance Pattern: AR

Disease ID:MONDO:0859304

Submitter: G2P

neurodegeneration, childhood-onset, with multisystem involvement due to mitochondrial dysfunctionSTRONG

Inheritance Pattern: AR

Disease ID:MONDO:0859304

Submitter: Labcorp Genetics (formerly Invitae)

Clinical Genomic Database (CGD)

Childhood-onset neurodegeneration with multisystem involvement due to mitochondrial dysfunctionAR

Manifestation: Audiologic/Otolaryngologic; Biochemical; Cardiovascular; Craniofacial; Endocrine; Musculoskeletal; Neurologic; Ophthalmologic

Intervention: Audiologic/Otolaryngologic; Cardiovascular

Rationale: 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

Refs: 36055214

Source: CGD (NHGRI)

ClinVar Associated Diseases & Phenotypes

Reported disease conditions connected to LETM1 variants in ClinVar

11 Conditions Cataloged

not providedTotal: 242

Inborn genetic diseasesTotal: 96

not specifiedTotal: 11

LETM1-associated clinical spectrum with predominant nervous system involvementTotal: 10

Neurodegeneration, childhood-onset, with multisystem involvement due to mitochondrial dysfunctionTotal: 10

LETM1-related disorderTotal: 7

4p partial monosomy syndromeTotal: 4

Global developmental delayTotal: 1

ClinVar Variants & Pathogenicity by Type

Statistics based on transcript NM_012318.3. 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			5 clinvar	92 clinvar	3 clinvar	100
missense	4 clinvar	1 clinvar	147 clinvar	12 clinvar	9 clinvar	173
nonsense			2 clinvar			2
start loss						0
frameshift	1 clinvar	3 clinvar	1 clinvar			5
splice donor/acceptor (+/-2bp)			5 clinvar			5
Total	5	4	160	104	12	285

Highest pathogenic variant AF is 0.00016376094

Loading ClinVar variants...

Transcript Catalog

Annotated transcript isoforms across RefSeq and Ensembl databases

Showing 4 of 41 transcripts

Transcript ID	Source	Protein ID	Coding Exons	MANE Status
NM_012318.3	RefSeq	NP_036450.1	14	MANE Select
ENST00000302787.3	Ensembl	ENSP00000305653.2	14	MANE Select
ENST00000872446.1	Ensembl	ENSP00000542505.1	14	Standard
ENST00000872446.2	Ensembl	ENSP00000542505.1	14	Standard

Gene Ontology (GO) Annotations & Pathways

Biological processes, molecular functions, cellular components and pathways

Pathways ConsensusPathDB

Transport of small molecules
Mitochondrial calcium ion transport

Biological Process

mitochondrial calcium ion transmembrane transport
protein hexamerization
cristae formation
protein homooligomerization
mitochondrial calcium ion homeostasis

Molecular Function

calcium ion binding
protein binding
calcium:proton antiporter activity
ribosome binding

Cellular Component

mitochondrion
mitochondrial inner membrane
integral component of membrane

gnomAD Constraint

Source: gnomAD

Gene type: protein_coding
Transcript type: protein_coding
Transcript: ENST00000302787
Coding exons: 14
Length: 44769
Individuals with no LoFs: 125682
Homozygous LoFs: 0
Heterozygous LoFs: 66
Defined: 125748
p: 0.000262

	Z-Score	Observed	Expected	Observed/Expected	Mutation Rate	Total Possible
Missense	1.58	341	433	0.787	0.0000281	4786
Missense (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

Population LoF Frequency

Population	CAF	p-value	Status
African	0.00025	0.00025	rare
Latino/Admixed American	0.00032	0.00032	rare
Ashkenazi Jewish	0.0014	0.0014	notable
East Asian	0.000054	0.000054	rare
Finnish	0.00014	0.00014	rare
European (Non-Finnish)	0.00020	0.00020	rare
South Asian	0.00029	0.00029	rare
Other	0.00016	0.00016	rare

dbNSFP Gene Annotations

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}.;

Recessive Scores

pRec: 0.0964

Intolerance Scores

LoFtool: 0.0849
RVIS EVS: 0.54
RVIS percentile EVS: 81.09

Essentials

Essential (CRISPR): E
Essential (CRISPR2): S
Essential (gene trap): E
Indispensability pred.: E
Indispensability score: 0.990

Gene Damage Prediction

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