MECR

protein-coding

mitochondrial trans-2-enoyl-CoA reductase

Gene summary

The protein encoded by this gene is an oxidoreductase that catalyzes the last step in mitochondrial fatty acid synthesis. Defects in this gene are a cause of childhood-onset dystonia and optic atrophy. [provided by RefSeq, Mar 2017]

MANE transcript

NM_016011.5

Inheritance

ClinVar variants

P:31U:103B:118

Top phenotype

Dystonia, childhood-onset, with optic atrophy and basal ganglia abnormalities; Optic atrophy 16

gnomAD constraint

pLI —, LoF o/e 0.51

Max pathogenic AF

—

Genomic locus

chr1:29,192,657-29,230,942

External References & Databases

Ensembl (ENSG00000116353)

Transcript & Mutation Effects

hg38 • Region Span ~38.3 kb

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GenCC Phenotypes & Disease Associations

Curated gene-disease validity assertions and inheritance patterns

dystonia, childhood-onset, with optic atrophy and basal ganglia abnormalitiesSTRONG

Inheritance Pattern: AR

Disease ID:MONDO:0015003

Submitter: PanelApp Australia

Leigh syndromeMODERATE

Inheritance Pattern: AR

Disease ID:MONDO:0009723

Submitter: ClinGen

The relationship between MECR and Leigh syndrome spectrum was evaluated using the ClinGen Clinical Validity Framework as of April 14, 2021. The MECR gene encodes mitochondrial trans-2-enoyl-coenzyme A-reductase which catalyzes the last step of the mitochondrial fatty acid synthesis pathway which is critical for normal function of the mitochondrial respiratory chain and several other mitochondrial enzyme complexes. The MECR gene was first reported in relation to autosomal recessive Leigh syndrome spectrum in 2016 (PMID: 27817865). Evidence supporting this gene-disease relationship includes case-level data and experimental data. This curation included five unique variants identified in three cases from one publication (PMID: 27817865). No segregation data were available. Loss of function is implicated as the mechanism of disease. This gene-disease association is also supported by known biochemical function, expression, and animal models (PMIDs: 27977873, 25613900, 30266742). In summary, there is moderate evidence to support this gene-disease relationship. While more evidence is needed to establish this relationship definitively, no convincing evidence has emerged that contradicts the gene-disease relationship. This classification was approved by the NICHD U24 ClinGen Mitochondrial Disease Gene Curation Expert Panel on April 14, 2021 (SOP Version 7).

dystonia, childhood-onset, with optic atrophy and basal ganglia abnormalitiesSTRONG

Inheritance Pattern: AR

Disease ID:MONDO:0015003

Submitter: G2P

dystonia, childhood-onset, with optic atrophy and basal ganglia abnormalitiesSTRONG

Inheritance Pattern: AR

Disease ID:MONDO:0015003

Submitter: Labcorp Genetics (formerly Invitae)

Clinical Genomic Database (CGD)

Dystonia, childhood-onset, with optic atrophy and basal ganglia abnormalities; Optic atrophy 16AR

Manifestation: Audiologic/Otolaryngologic; Neurologic; Ophthalmologic

Intervention: General

Rationale: Genetic knowledge may be beneficial related to issues such as selection of optimal supportive care, informed medical decision-making, prognostic considerations, and avoidance of unnecessary testing

Refs: 27817865; 37734847

Source: CGD (NHGRI)

ClinVar Associated Diseases & Phenotypes

Reported disease conditions connected to MECR variants in ClinVar

10 Conditions Cataloged

not providedTotal: 286

Inborn genetic diseasesTotal: 62

not specifiedTotal: 23

Dystonia, childhood-onset, with optic atrophy and basal ganglia abnormalitiesTotal: 16

MECR-related disorderTotal: 14

Childhood Onset DystoniasTotal: 6

Optic atrophyTotal: 6

MECR-related disordersTotal: 5

ClinVar Variants & Pathogenicity by Type

Statistics based on transcript NM_016011.5. 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				103 clinvar		103
missense	2 clinvar	3 clinvar	99 clinvar	15 clinvar		119
nonsense	7 clinvar	1 clinvar	3 clinvar			11
start loss						0
frameshift	10 clinvar	1 clinvar				11
splice donor/acceptor (+/-2bp)		7 clinvar	1 clinvar			8
Total	19	12	103	118	0	252

Highest pathogenic variant AF is 0.000080559905

Loading ClinVar variants...

Transcript Catalog

Annotated transcript isoforms across RefSeq and Ensembl databases

Showing 4 of 48 transcripts

Transcript ID	Source	Protein ID	Coding Exons	MANE Status
NM_016011.5	RefSeq	NP_057095.4	10	MANE Select
ENST00000263702.11	Ensembl	ENSP00000263702.6	10	MANE Select
NM_001024732.4	RefSeq	NP_001019903.3	9	Standard
NM_001349711.2	RefSeq	NP_001336640.1	9	Standard

Gene Ontology (GO) Annotations & Pathways

Biological processes, molecular functions, cellular components and pathways

Pathways ConsensusPathDB

Fatty acid elongation - Homo sapiens (human)
Long-chain-3-hydroxyacyl-coa dehydrogenase deficiency (LCHAD)
Fatty Acid Elongation In Mitochondria
Fatty Acid Biosynthesis
Liver steatosis AOP

Biological Process

fatty acid metabolic process
fatty acid biosynthetic process
fatty acid beta-oxidation

Molecular Function

trans-2-enoyl-CoA reductase (NADPH) activity

Cellular Component

nucleus
mitochondrion
mitochondrial matrix

gnomAD Constraint

Source: gnomAD

Gene type: protein_coding
Transcript type: protein_coding
Transcript: ENST00000263702
Coding exons: 10
Length: 38070
Individuals with no LoFs: 125703
Homozygous LoFs: 0
Heterozygous LoFs: 45
Defined: 125748
p: 0.000179

	Z-Score	Observed	Expected	Observed/Expected	Mutation Rate	Total Possible
Missense	0.111	214	219	0.979	0.0000120	2386
Missense (PolyPhen)		39	47.757	0.81664		559
Synonymous	-0.773	98	88.7	1.10	0.00000515	778
Loss of Function	2.09	11	21.5	0.512	0.00000117	211

Population LoF Frequency

Population	CAF	p-value	Status
African	0.00031	0.00031	rare
Latino/Admixed American	0.00024	0.00023	rare
Ashkenazi Jewish	0	0.0	absent
East Asian	0.00012	0.00011	rare
Finnish	0.00014	0.00014	rare
European (Non-Finnish)	0.00014	0.00014	rare
South Asian	0.00034	0.00033	rare
Other	0.00016	0.00016	rare

dbNSFP Gene Annotations

Source: dbNSFP

Function: FUNCTION: Catalyzes the NADPH-dependent reduction of trans-2-enoyl thioesters in mitochondrial fatty acid synthesis (fatty acid synthesis type II). Fatty acid chain elongation in mitochondria uses acyl carrier protein (ACP) as an acyl group carrier, but the enzyme accepts both ACP and CoA thioesters as substrates in vitro. Has a preference for short and medium chain substrates, including trans-2-hexenoyl-CoA (C6), trans-2-decenoyl-CoA (C10), and trans- 2-hexadecenoyl-CoA (C16). {ECO:0000269|PubMed:18479707, ECO:0000269|PubMed:27817865}.;

Recessive Scores

pRec: 0.111

Intolerance Scores

LoFtool: 0.870
RVIS EVS: 0.71
RVIS percentile EVS: 85.63

Essentials

Essential (CRISPR): E
Essential (CRISPR2): E
Essential (gene trap): N
Indispensability pred.: N
Indispensability score: 0.0583

Gene Damage Prediction

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