ELAC2

protein-coding

elaC ribonuclease Z 2, the group of Endoribonucleases|MBL fold containing DNA/RNA interacting subfamily

Gene summary

The protein encoded by this gene has a C-terminal domain with tRNA 3′ processing endoribonuclease activity, which catalyzes the removal of the 3' trailer from precursor tRNAs. The protein also interacts with activated Smad family member 2 (Smad2) and its nuclear partner forkhead box H1 (also known as FAST-1), and reduced expression can suppress transforming growth factor-beta induced growth arrest. Mutations in this gene result in an increased risk of prostate cancer. Multiple transcript variants encoding different isoforms have been found for this gene. [provided by RefSeq, Sep 2009]

MANE transcript

NM_018127.7

Inheritance

ClinVar variants

P:93U:424B:318

Top phenotype

Combined oxidative phosphorylation deficiency 17

gnomAD constraint

pLI —, LoF o/e 0.79

Max pathogenic AF

—

Genomic locus

chr17:12,991,612-13,018,065

External References & Databases

Ensembl (ENSG00000006744)

Transcript & Mutation Effects

hg38 • Region Span ~26.5 kb

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GenCC Phenotypes & Disease Associations

Curated gene-disease validity assertions and inheritance patterns

combined oxidative phosphorylation defect type 17STRONG

Inheritance Pattern: AR

Disease ID:MONDO:0014190

Submitter: PanelApp Australia

combined oxidative phosphorylation defect type 17DEFINITIVE

Inheritance Pattern: AR

Disease ID:MONDO:0014190

Submitter: G2P

combined oxidative phosphorylation defect type 17SUPPORTIVE

Inheritance Pattern: AR

Disease ID:MONDO:0014190

Submitter: Orphanet

combined oxidative phosphorylation defect type 17STRONG

Inheritance Pattern: AR

Disease ID:MONDO:0014190

Submitter: Labcorp Genetics (formerly Invitae)

mitochondrial diseaseDEFINITIVE

Inheritance Pattern: AR

Disease ID:MONDO:0044970

Submitter: ClinGen

The relationship between *ELAC2* and primary mitochondrial disease was evaluated using the ClinGen Clinical Validity Framework as of July 21, 2022. The *ELAC2* gene encodes the elaC ribonuclease Z 2 that is involved in mitochondrial RNA expression and processing, and is essential for tRNA maturation. The *ELAC2* gene was first reported in relation to autosomal recessive primary mitochondrial disease in 2013 (PMID: 23849775). While various names have been given to the constellation of features seen in those with *ELAC2*-related disease, pathogenic variants in this gene cause a primary mitochondrial disease. Therefore, the *ELAC2* phenotype has been lumped into one disease entity according to per the ClinGen Lumping and Splitting Framework. Evidence supporting this gene-disease relationship includes case-level data and experimental data. This curation included 15 variants (one nonsense, 11 missense, 3 splice site) from 10 individuals from two publications (PMIDs: 23849775, 31045291). More cases are reported in the medical literature but not included in this curation as the maximum case level score was reached. Affected individuals are variably affected and clinical features include hypertrophic cardiomyopathy, intrauterine growth restriction, developmental delay, hypotonia, muscle weakness, exercise intolerance, microcephaly, feeding difficulty, sensorineural hearing loss, and lactic acidosis. Muscle biopsies show mitochondria with increased size and abnormal cristae, ragged red fibers, COX-negative fibers, and variable respiratory chain enzyme complex deficiencies. A heart transplant was successful in at least one individual (PMID: 31045291). Loss of function is the mechanism of disease. This gene-disease association is also supported by known biochemical function, functional alteration in patient cells, and model systems in mice and *Drosophila melanogaster* (PMIDs: 21593607, 23849775, 21146608, 34338278, 30126926). In summary, there is definitive evidence to support this gene-disease relationship, including that more than three years have elapsed since the first proposal of the association. No convincing evidence has emerged that contradicts the gene-disease relationship. This classification was approved by the NICHD/NINDS U24 ClinGen Mitochondrial Disease Gene Curation Expert Panel on July 21, 2022 (SOP Version 8).

Clinical Genomic Database (CGD)

Combined oxidative phosphorylation deficiency 17AR

Manifestation: Biochemical; Cardiovascular; Neurologic

Intervention: Biochemical; Cardiovascular

Rationale: The condition can include severe cardiac sequelae, such as hypertrophic cardiomyopathy, and though some individuals have been described as not responding to therapy, others have been reported as benefitting from cardiac surveillance and early insitution of cardioprotective therapy and and biochemical dietary and medical treatment (eg, high-fat diet, coenzyme Q10, riboflavin, thiamine, and carnitine)

Refs: 23849775

Source: CGD (NHGRI)

ClinVar Associated Diseases & Phenotypes

Reported disease conditions connected to ELAC2 variants in ClinVar

11 Conditions Cataloged

Combined oxidative phosphorylation defect type 17Total: 1051

not providedTotal: 168

Inborn genetic diseasesTotal: 113

not specifiedTotal: 92

Prostate cancer, hereditary, 2Total: 30

ELAC2-related disorderTotal: 29

ELAC2-related disordersTotal: 9

Ovarian cancerTotal: 6

ClinVar Variants & Pathogenicity by Type

Statistics based on transcript NM_018127.7. 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			7 clinvar	290 clinvar	3 clinvar	300
missense	3 clinvar	12 clinvar	395 clinvar	23 clinvar	1 clinvar	434
nonsense	17 clinvar	10 clinvar	3 clinvar			30
start loss						0
frameshift	23 clinvar	4 clinvar	5 clinvar			32
splice donor/acceptor (+/-2bp)	1 clinvar	23 clinvar	14 clinvar	1 clinvar		39
Total	44	49	424	314	4	835

Highest pathogenic variant AF is 0.00089995144

Loading ClinVar variants...

Transcript Catalog

Annotated transcript isoforms across RefSeq and Ensembl databases

Showing 4 of 80 transcripts

Transcript ID	Source	Protein ID	Coding Exons	MANE Status
NM_018127.7	RefSeq	NP_060597.4	24	MANE Select
ENST00000338034.9	Ensembl	ENSP00000337445.4	24	MANE Select
NM_001165962.2	RefSeq	NP_001159434.1	23	Standard
NM_173717.2	RefSeq	NP_776065.1	24	Standard

Gene Ontology (GO) Annotations & Pathways

Biological processes, molecular functions, cellular components and pathways

Pathways ConsensusPathDB

RNA transport - Homo sapiens (human)
tRNA processing
Metabolism of RNA
tRNA processing in the nucleus

Biological Process

tRNA 3'-end processing
mitochondrial tRNA 3'-trailer cleavage, endonucleolytic
mitochondrial tRNA processing

Molecular Function

RNA binding
endonuclease activity
tRNA-specific ribonuclease activity
metal ion binding

Cellular Component

nucleus
nucleoplasm
mitochondrion
mitochondrial matrix
mitochondrial nucleoid

gnomAD Constraint

Source: gnomAD

Gene type: protein_coding
Transcript type: protein_coding
Transcript: ENST00000338034
Coding exons: 24
Length: 25797
Individuals with no LoFs: 125450
Homozygous LoFs: 1
Heterozygous LoFs: 297
Defined: 125748
p: 0.00119

	Z-Score	Observed	Expected	Observed/Expected	Mutation Rate	Total Possible
Missense	-0.410	479	454	1.05	0.0000268	5359
Missense (PolyPhen)		164	163.82	1.0011		1918
Synonymous	-2.25	219	180	1.21	0.0000114	1605
Loss of Function	1.30	36	45.5	0.792	0.00000236	523

Population LoF Frequency

Population	CAF	p-value	Status
African	0.011	0.011	notable
Latino/Admixed American	0.00055	0.00055	rare
Ashkenazi Jewish	0	0.0	absent
East Asian	0.00049	0.00049	rare
Finnish	0.00065	0.00065	rare
European (Non-Finnish)	0.00062	0.00057	rare
South Asian	0.00049	0.00049	rare
Other	0.00082	0.00081	rare

dbNSFP Gene Annotations

Source: dbNSFP

Function: FUNCTION: Zinc phosphodiesterase, which displays mitochondrial tRNA 3'-processing endonuclease activity. Involved in tRNA maturation, by removing a 3'-trailer from precursor tRNA. {ECO:0000269|PubMed:21593607}.;
Disease: DISEASE: Combined oxidative phosphorylation deficiency 17 (COXPD17) [MIM:615440]: An autosomal recessive disorder of mitochondrial dysfunction characterized by onset of severe hypertrophic cardiomyopathy in the first year of life. Other features include hypotonia, poor growth, lactic acidosis, and failure to thrive. The disorder may be fatal in early childhood. {ECO:0000269|PubMed:23849775}. Note=The disease is caused by mutations affecting the gene represented in this entry.;

Recessive Scores

pRec: 0.0979

Intolerance Scores

LoFtool: 0.929
RVIS EVS: -0.91
RVIS percentile EVS: 10.12

Essentials

Essential (CRISPR): E
Essential (CRISPR2): E
Essential (gene trap): E
Indispensability pred.: N
Indispensability score: 0.485

Gene Damage Prediction

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