ISCA2
protein-codingiron-sulfur cluster assembly 2, the group of Mitochondrial iron-sulfur assembly components
Gene summary
The protein encoded by this gene is an A-type iron-sulfur cluster (ISC) protein found in mitochondria. The encoded protein appears to be involved in the maturation of mitochondrial iron-sulfur proteins. Two transcript variants encoding different isoforms have been found for this gene. [provided by RefSeq, Dec 2012]
- HBLD1
MANE transcript
Inheritance
ClinVar variants
Top phenotype
gnomAD constraint
Max pathogenic AF
Genomic locus
External References & Databases
Transcript & Mutation Effects
hg38 • Region Span ~3.4 kbGenCC Phenotypes & Disease Associations
Curated gene-disease validity assertions and inheritance patterns
Inheritance Pattern: AR
Disease ID:MONDO:0014611
Submitter: Orphanet
Inheritance Pattern: AR
Disease ID:MONDO:0014611
Submitter: Labcorp Genetics (formerly Invitae)
Inheritance Pattern: AR
Disease ID:MONDO:0044970
Submitter: ClinGen
The relationship between *ISCA2* and primary mitochondrial disease was evaluated using the ClinGen Clinical Validity Framework as of August 21, 2023. *ISCA2* encodes the protein iron-sulfur cluster assembly 2 that, along with *ISCA1* and *IBA57*, is part of the iron-sulfur cluster (ISC) assembly machinery in mitochondria functioning late (maturation) in the biosynthetic pathway of mitochondrial 4Fe-4S proteins. *ISCA2* was first reported in relation to autosomal recessive primary mitochondrial disease in 2015 (PMID: 25539947), in several individuals with infantile-onset neurodegeneration and severe leukodystrophy. While various names have been given to the constellation of features seen in those with *ISCA2*-related disease, pathogenic variants in this gene cause a primary mitochondrial disease. Therefore, the *ISCA2* phenotype has been lumped into one disease entity according to the ClinGen Lumping and Splitting Framework. Evidence supporting this gene-disease relationship includes case-level data and experimental data. This curation included eight unique variants (seven missense, one frameshift) identified in twenty-one probands from eight publications (PMIDs: 25539947, 25558065, 28803783, 29297947, 29122497, 29359243, 31279336, 32424628). One of the seven missense variants was a founder variant, c.229G>A (p.Gly77Ser; NM_194279.4) that was seen in the homozygous state in 16 probands of Saudi Arabian descent. Affected individuals commonly present in the infantile period with regression, nystagmus/optic atrophy, and white matter involvement, and most reported individuals died in early childhood. There is one report of a more mildly affected individual with spastic paraplegia (PMID: 28803783). Muscle biopsies in affected individuals were variable, including variable mitochondrial respiratory chain enzyme activities. Brain imaging generally showed diffuse bilateral symmetric signal abnormality in cerebral white matter with variable involvement of other parts of the brain. Metabolic labs showed variable elevated blood and cerebrospinal fluid lactate and glycine. This gene-disease association is also supported by its known biochemical function (PMID: 33340416) and functional alteration in non-patient cells (PMIDs: 29297947, 22323289). In summary, there is definitive evidence to support the relationship between *ISCA2* and primary mitochondrial disease. This has been repeatedly demonstrated and upheld over time, and no convincing evidence has emerged that contradicts this gene-disease relationship. This classification was approved by the NICHD/NINDS U24 ClinGen Mitochondrial Disease Gene Curation Expert Panel on August 21, 2023 (SOP Version 9).
Inheritance Pattern: AR
Disease ID:MONDO:0014611
Submitter: Ambry Genetics
Inheritance Pattern: AR
Disease ID:MONDO:0014611
Submitter: PanelApp Australia
Inheritance Pattern: AR
Disease ID:MONDO:0014611
Submitter: Genomics England PanelApp
Clinical Genomic Database (CGD)
Manifestation: Biochemical; Musculoskeletal; 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; Variants may additionally act as susceptibility factors (rather than being involved in Mendelian-inherited dominant disease)
ClinVar Associated Diseases & Phenotypes
Reported disease conditions connected to ISCA2 variants in ClinVar
ClinVar Variants & Pathogenicity by Type
Statistics based on transcript NM_194279.4. 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 | 1 | 19 | 20 | |||
| missense | 3 | 43 | 3 | 49 | ||
| nonsense | 1 | 1 | 2 | |||
| start loss | 0 | |||||
| frameshift | 2 | 2 | 4 | |||
| splice donor/acceptor (+/-2bp) | 0 | |||||
| Total | 1 | 6 | 46 | 22 | 0 | 75 |
Highest pathogenic variant AF is 0.00006630659
Transcript Catalog
Annotated transcript isoforms across RefSeq and Ensembl databases
| Transcript ID | Source | Protein ID | Coding Exons | MANE Status |
|---|---|---|---|---|
| RefSeq | NP_919255.2 | 4 | MANE Select | |
| Ensembl | ENSP00000452007.1 | 4 | MANE Select | |
| RefSeq | NP_001258936.1 | 3 | Standard | |
| Ensembl | ENSP00000298818.8 | 4 | Standard |
Gene Ontology (GO) Annotations & Pathways
Biological processes, molecular functions, cellular components and pathways
Pathways ConsensusPathDB
- Mitochondrial iron-sulfur cluster biogenesis
- Metabolism
Biological Process
- iron-sulfur cluster assembly
- small molecule metabolic process
- protein maturation
- protein maturation by iron-sulfur cluster transfer
- protein maturation by [4Fe-4S] cluster transfer
Molecular Function
- structural molecule activity
- iron ion binding
- protein binding
- 2 iron, 2 sulfur cluster binding
- 4 iron, 4 sulfur cluster binding
Cellular Component
- mitochondrion
- mitochondrial matrix
gnomAD Constraint
Source:
- Gene type
- protein_coding
- Transcript type
- protein_coding
- Transcript
- ENST00000556816
- Coding exons
- 4
- Length
- 3387
- Individuals with no LoFs
- 125725
- Homozygous LoFs
- 0
- Heterozygous LoFs
- 23
- Defined
- 125748
- p
- 0.0000915
| Z-Score | Observed | Expected | Observed/Expected | Mutation Rate | Total Possible | |
|---|---|---|---|---|---|---|
| Missense | 0.384 | 71 | 80.7 | 0.880 | 0.00000366 | 971 |
| Missense (PolyPhen) | 20 | 25.615 | 0.78078 | 319 | ||
| Synonymous | -1.12 | 43 | 34.6 | 1.24 | 0.00000165 | 318 |
| Loss of Function | -1.01 | 10 | 7.09 | 1.41 | 3.54e-7 | 75 |
Population LoF Frequency
| Population | CAF | p-value | Status |
|---|---|---|---|
| African | 0.000062 | 0.000062 | rare |
| Latino/Admixed American | 0.00017 | 0.00017 | rare |
| Ashkenazi Jewish | 0 | 0.0 | absent |
| East Asian | 0.00023 | 0.00022 | rare |
| Finnish | 0.000046 | 0.000046 | rare |
| European (Non-Finnish) | 0.000079 | 0.000079 | rare |
| South Asian | 0 | 0.0 | absent |
| Other | 0.00035 | 0.00033 | rare |
dbNSFP Gene Annotations
Source:
- Function
- FUNCTION: Involved in the maturation of mitochondrial 4Fe-4S proteins functioning late in the iron-sulfur cluster assembly pathway. May be involved in the binding of an intermediate of Fe/S cluster assembly. {ECO:0000269|PubMed:22323289}.;
- Disease
- DISEASE: Multiple mitochondrial dysfunctions syndrome 4 (MMDS4) [MIM:616370]: A severe disorder of systemic energy metabolism, resulting in weakness, respiratory failure, lack of neurologic development, lactic acidosis, hyperglycinemia and early death. {ECO:0000269|PubMed:25539947}. Note=The disease is caused by mutations affecting the gene represented in this entry.;
Intolerance Scores
- LoFtool
- 0.530
- RVIS EVS
- 0.08
- RVIS percentile EVS
- 59.43
Essentials
- Essential (CRISPR)
- E
- Essential (CRISPR2)
- S
- Essential (gene trap)
- H
- Indispensability pred.
- N
- Indispensability score
- 0.114
Gene Damage Prediction
| All | Recessive | Dominant | |
|---|---|---|---|
| Mendelian | Medium | Medium | Medium |
| Primary Immunodeficiency | Medium | Medium | Medium |
| Cancer | Medium | Medium | Medium |