TECRL
protein-codingtrans-2,3-enoyl-CoA reductase like, the group of Steroid 5-alpha reductase family
Gene summary
The protein encoded by this gene contains a ubiquitin-like domain in the N-terminal region, three transmembrane segments and a C-terminal 3-oxo-5-alpha steroid 4-dehydrogenase domain. The protein belongs to the steroid 5-alpha reductase family. Mutations in this gene result in ventricular tachycardia, catecholaminergic polymorphic, 3. [provided by RefSeq, Apr 2017]
MANE transcript
Inheritance
ClinVar variants
Top phenotype
gnomAD constraint
Max pathogenic AF
Genomic locus
External References & Databases
Transcript & Mutation Effects
hg38 • Region Span ~134.2 kbGenCC Phenotypes & Disease Associations
Curated gene-disease validity assertions and inheritance patterns
Inheritance Pattern: AR
Disease ID:MONDO:0013529
Submitter: G2P
Inheritance Pattern: AR
Disease ID:MONDO:0013529
Submitter: PanelApp Australia
Inheritance Pattern: AR
Disease ID:MONDO:0013529
Submitter: Genomics England PanelApp
Inheritance Pattern: AR
Disease ID:MONDO:0013529
Submitter: Labcorp Genetics (formerly Invitae)
Inheritance Pattern: AR
Disease ID:MONDO:0013529
Submitter: Ambry Genetics
Inheritance Pattern: AR
Disease ID:MONDO:0017990
Submitter: ClinGen
TECRL was evaluated for autosomal recessive catecholaminergic polymorphic ventricular tachycardia (CPVT). Biallelic loss of function variants in TECRL were first reported in 2016 (Devalla et al, 2016, PMID:27861123), with a homozygous missense variant (p.Arg196Gln) detected in two unrelated patients of French Canadian origin and a homozygous splice donor variant (c.331+1G>A) detected in a large consanguineous Sudanese pedigree where 7/13 children (all homozygous) has exercise-induces arrhythmias or sudden cardiac death (LOD=4.36). Another report described compound heterozygous variants in a 13 year old child with CPVT (p.Arg196Gln and c.918+3T>G), although the effect of the splice region variant was not proven (Xie et al, 2019, PMID:30790670). A multi-centre review published in 2020 provided an update on these cases and described two additional CPVT cases (homozygous p.Tyr197Ter nonsense variant and homozygous exon 2 deletion) and a family with three children with sudden cardiac death, where one was homozygous for the c.331+1G>A splice donor variant (Webster et al, 2020, PMID:33367594). Finally, another study described 4 CPVT cases with TECRL variants detected by diagnostic sequencing, including homozygous missense (p.Pro290His) and nonsense variants (p.Gln139Ter), compound heterozygous variants (p.Ser309Ter/p.Val298Ala) and a large homozygous duplication that covered the TECRL gene (the effect of this variant on TECRL gene expression is unknown and the scoring was downgraded accordingly) (Mosku-Gregor et al, 2020, PMID:32173957). These cases presented with phenotypic features typical of CPVT, including exercise and emotion induced syncope and cardiac arrest and ventricular arrhythmias during exercise testing. A mild prolonged QT interval was observed in several cases, especially after stimulation by epinephrine or exercise, although overall the phenotypes are much more typical of CPVT than LQTS. The association of TECRL with CPVT is also supported by experimental evidence with clear functional effects observed in iPSC derived cardiomyocytes generated from a patient with the homozygous c.331+1G>A variant. In summary, TECRL variants are definitively associated with autosomal recessive CPVT. Note: All CPVT genes were curated by 3 separate blinded teams. The evidence and scores reached by these 3 teams was reviewed by the CPVT Gene Curation Expert Panel (GCEP). The classification and summary presented here is the conclusion of this GCEP's analysis according to evidence teams' efforts. This classification was approved by the ClinGen Catecholaminergic Polymorphic Ventricular Tachycardia Gene Curation Expert Panel on 20th January, 2021 (SOP Version 7).
Clinical Genomic Database (CGD)
Manifestation: Cardiovascular
Intervention: Cardiovascular
Rationale: The condition can include cardiac arrest and sudden cardiac death, and medical and surgical interventions (eg, with ICD) has been described as beneficial
ClinVar Associated Diseases & Phenotypes
Reported disease conditions connected to TECRL variants in ClinVar
ClinVar Variants & Pathogenicity by Type
Statistics based on transcript NM_001010874.5. 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 | 3 | 70 | 73 | |||
| missense | 2 | 190 | 25 | 217 | ||
| nonsense | 5 | 3 | 1 | 9 | ||
| start loss | 0 | |||||
| frameshift | 5 | 5 | 1 | 11 | ||
| splice donor/acceptor (+/-2bp) | 9 | 9 | ||||
| Total | 10 | 19 | 195 | 95 | 0 | 319 |
Highest pathogenic variant AF is 0.0000607821
Transcript Catalog
Annotated transcript isoforms across RefSeq and Ensembl databases
| Transcript ID | Source | Protein ID | Coding Exons | MANE Status |
|---|---|---|---|---|
| RefSeq | NP_001010874.2 | 12 | MANE Select | |
| Ensembl | ENSP00000370607.3 | 12 | MANE Select | |
| RefSeq | NP_001350725.1 | 12 | Standard | |
| Ensembl | ENSP00000426043.1 | 12 | Standard |
Gene Ontology (GO) Annotations & Pathways
Biological processes, molecular functions, cellular components and pathways
Pathways ConsensusPathDB
- Metabolism of lipids
- Fatty acyl-CoA biosynthesis
- Metabolism
- Fatty acid metabolism
- Synthesis of very long-chain fatty acyl-CoAs
Biological Process
- very long-chain fatty acid biosynthetic process
- oxidation-reduction process
Molecular Function
- oxidoreductase activity
- oxidoreductase activity, acting on the CH-CH group of donors
Cellular Component
- endoplasmic reticulum
- integral component of membrane
gnomAD Constraint
Source:
- Gene type
- protein_coding
- Transcript type
- protein_coding
- Transcript
- ENST00000381210
- Coding exons
- 12
- Length
- 134212
- Individuals with no LoFs
- 125689
- Homozygous LoFs
- 0
- Heterozygous LoFs
- 57
- Defined
- 125746
- p
- 0.000227
| Z-Score | Observed | Expected | Observed/Expected | Mutation Rate | Total Possible | |
|---|---|---|---|---|---|---|
| Missense | -0.415 | 197 | 181 | 1.09 | 0.00000876 | 2348 |
| Missense (PolyPhen) | 69 | 61.355 | 1.1246 | 837 | ||
| Synonymous | -0.573 | 66 | 60.3 | 1.09 | 0.00000279 | 650 |
| Loss of Function | 0.448 | 19 | 21.2 | 0.895 | 0.00000103 | 270 |
Population LoF Frequency
| Population | CAF | p-value | Status |
|---|---|---|---|
| African | 0.00031 | 0.00031 | rare |
| Latino/Admixed American | 0.000064 | 0.000058 | rare |
| Ashkenazi Jewish | 0 | 0.0 | absent |
| East Asian | 0.00040 | 0.00038 | rare |
| Finnish | 0.000046 | 0.000046 | rare |
| European (Non-Finnish) | 0.00026 | 0.00025 | rare |
| South Asian | 0.00046 | 0.00046 | rare |
| Other | 0 | 0.0 | absent |
dbNSFP Gene Annotations
Source:
Intolerance Scores
- LoFtool
- 0.868
- RVIS EVS
- 0.33
- RVIS percentile EVS
- 73.41
Essentials
- Essential (CRISPR)
- N
- Essential (CRISPR2)
- N
- Essential (gene trap)
- N
- Indispensability pred.
- N
- Indispensability score
- 0.0971
Gene Damage Prediction
| All | Recessive | Dominant | |
|---|---|---|---|
| Mendelian | Medium | Medium | Medium |
| Primary Immunodeficiency | Medium | Medium | Medium |
| Cancer | Medium | Medium | Medium |