ISCU

iron-sulfur cluster assembly enzyme, the group of Mitochondrial iron-sulfur assembly components

Basic information

Region (hg38): 12:108562581-108569368

Previous symbols: [ "NIFUN" ]

Links

ENSG00000136003 ∙ NCBI:23479 ∙ OMIM:611911 ∙ HGNC:29882 ∙ Uniprot:Q9H1K1 ∙ AlphaFold ∙ GenCC ∙ jax ∙ Sfari ∙ GnomAD ∙ Pubmed ∙ ClinVar

Phenotypes

GenCC

Source: genCC

• hereditary myopathy with lactic acidosis due to ISCU deficiency (Strong), mode of inheritance: AR
• hereditary myopathy with lactic acidosis due to ISCU deficiency (Supportive), mode of inheritance: AR
• mitochondrial disease (Definitive), mode of inheritance: AR

Clinical Genomic Database

Source: CGD

Condition	Inheritance	Intervention Categories	Intervention/Rationale	Manifestation Categories	References
Myopathy with lactic acidosis, hereditary	AR	Musculoskeletal; Renal	In addition to cardiovascular features, the condition can include rhabdomyolysis, and appropriate precautions and prompt recognition may be beneficial	Cardiovascular; Musculoskeletal; Renal	14213465; 5811159; 2384736; 18304497; 18296749; 19846308; 20206689
Treatment (using an antisense phosphorodiamidate morpholino oligonucleotide) of cultured fibroblasts from three individuals with a homozygous splice-site variant resulted in restoration of the normal splicing pattern

ClinVar

This is a list of variants' phenotypes submitted to ClinVar and linked to the ISCU gene.

• not provided (1 variants)
• Hereditary myopathy with lactic acidosis due to ISCU deficiency (1 variants)

Variants pathogenicity by type

Statistics on ClinVar variants can assist in determining whether a specific variant type in the ISCU gene is commonly pathogenic or not.

In the table, we include only reliable ClinVar variants with their consequences to MANE Select, Mane Plus Clinical transcripts, or transcripts with TSL equals 1. Click the count to view the source variants.

Warning: slight differences between displayed counts and the number of variants in ClinVar may occur, primarily due to (1) the application of a different transcript and/or consequence by our variant effect predictor or (2) differences in clinical significance: we classify Benign/Likely benign variants as Likely benign and Pathogenic/Likely pathogenic variants as Likely pathogenic.

Variant type	Pathogenic	Likely pathogenic	VUS	Likely benign	Benign	Sum
synonymous				28	2	30
missense		1	41	2	3	47
nonsense			1			1
start loss						0
frameshift			2			2
inframe indel						0
splice donor/acceptor (+/-2bp)			1			1
splice region			2	4	1	7
non coding	1		4	32	25	62
Total	1	1	49	62	30

Highest pathogenic variant AF is 0.00000657

Variants in ISCU

This is a list of pathogenic ClinVar variants found in the ISCU region.

You can filter this list by clicking the number of variants in the Variants pathogenicity by type table.

Position	Type	Phenotype	Significance	ClinVar
12-108562604-G-T		not specified	Likely benign (Jun 14, 2017)
12-108562627-C-T			Uncertain significance (Jul 12, 2022)
12-108562631-G-A			Likely benign (Apr 14, 2023)
12-108562632-G-C		Hereditary myopathy with lactic acidosis due to ISCU deficiency • ISCU-related disorder	Conflicting classifications of pathogenicity (Feb 01, 2024)
12-108562634-T-G			Likely benign (Jun 01, 2022)
12-108562636-G-C			Uncertain significance (Aug 14, 2022)
12-108562637-G-A			Likely benign (Mar 17, 2023)
12-108562637-G-C			Likely benign (Oct 17, 2023)
12-108562637-G-T			Likely benign (Sep 06, 2023)
12-108562639-C-T			Uncertain significance (Aug 03, 2021)
12-108562641-T-G		Hereditary myopathy with lactic acidosis due to ISCU deficiency	Benign (Jan 23, 2024)
12-108562641-TT-GG		Hereditary myopathy with lactic acidosis due to ISCU deficiency	Benign (Feb 01, 2024)
12-108562641-TTC-GGT			Uncertain significance (Jul 26, 2022)
12-108562642-T-G		Hereditary myopathy with lactic acidosis due to ISCU deficiency	Benign (Jan 23, 2024)
12-108562644-C-A			Uncertain significance (Jul 11, 2022)
12-108562644-C-G			Uncertain significance (May 27, 2022)
12-108562644-C-T		Inborn genetic diseases	Uncertain significance (Jan 17, 2024)
12-108562647-C-T			Benign (Jan 22, 2024)
12-108562649-G-A			Likely benign (Nov 08, 2022)
12-108562649-G-C			Likely benign (Apr 12, 2022)
12-108562649-G-T		not specified	Benign (Jan 29, 2024)
12-108562651-G-A			Uncertain significance (Nov 08, 2022)
12-108562652-G-A			Likely benign (Jun 04, 2021)
12-108562653-C-T			Uncertain significance (Jul 11, 2022)
12-108562654-G-C		Inborn genetic diseases	Uncertain significance (Aug 04, 2023)

GnomAD

Source: gnomAD

Gene	Type	Bio Type	Transcript	Coding Exons	Length
ISCU	protein_coding	protein_coding	ENST00000311893	5	6803

pLI Probability LOF Intolerant	pRec Probability LOF Recessive	Individuals with no LOFs	Individuals with Homozygous LOFs	Individuals with Heterozygous LOFs	Defined	p
0.0415	0.854	125739	0	9	125748	0.0000358

	Z-Score	Observed	Expected	Observed/Expected	Mutation Rate	Total Possible in Transcript
Missense	0.207	77	82.3	0.936	0.00000424	1026
Missense in Polyphen		32	48.449	0.66049		557
Synonymous	-0.927	42	35.0	1.20	0.00000204	332
Loss of Function	1.32	3	6.69	0.449	2.84e-7	93

LoF frequencies by population

Ethnicity	Sum of pLOFs	p
African & African-American	0.000148	0.000148
Ashkenazi Jewish	0.00	0.00
East Asian	0.00	0.00
Finnish	0.00	0.00
European (Non-Finnish)	0.0000352	0.0000352
Middle Eastern	0.00	0.00
South Asian	0.0000327	0.0000327
Other	0.00	0.00

dbNSFP

Source: dbNSFP

• Function: FUNCTION: Scaffold protein for the de novo synthesis of iron- sulfur (Fe-S) clusters within mitochondria, which is required for maturation of both mitochondrial and cytoplasmic [2Fe-2S] and [4Fe-4S] proteins (PubMed:11060020). First, a [2Fe-2S] cluster is transiently assembled on the scaffold protein ISCU. In a second step, the cluster is released from ISCU, transferred to a glutaredoxin GLRX5, followed by the formation of mitochondrial [2Fe-2S] proteins, the synthesis of [4Fe-4S] clusters and their target-specific insertion into the recipient apoproteins. Cluster assembly on ISCU depends on the function of the cysteine desulfurase complex NFS1-LYRM4/ISD11, which serves as the sulfur donor for cluster synthesis, the iron-binding protein frataxin as the putative iron donor, and the electron transfer chain comprised of ferredoxin reductase and ferredoxin, which receive their electrons from NADH (By similarity). {ECO:0000250|UniProtKB:Q03020, ECO:0000269|PubMed:11060020}.
• Pathway: Mitochondrial iron-sulfur cluster biogenesis;Metabolism (Consensus)

Recessive Scores

• pRec: 0.193

Intolerance Scores

• loftool: 0.304
• rvis_EVS: 0.06
• rvis_percentile_EVS: 58

Haploinsufficiency Scores

• pHI: 0.454
• hipred: N
• hipred_score: 0.444
• ghis: 0.586

Essentials

• essential_gene_CRISPR: E
• essential_gene_CRISPR2: E
• essential_gene_gene_trap: E
• gene_indispensability_pred: E
• gene_indispensability_score: 0.860

Gene Damage Prediction

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

Mouse Genome Informatics

• Gene name: Iscu

Gene ontology

• Biological process: cellular iron ion homeostasis;iron-sulfur cluster assembly;small molecule metabolic process
• Cellular component: nucleus;cytoplasm;mitochondrion;mitochondrial matrix;cytosol
• Molecular function: iron ion binding;protein binding;ferrous iron binding;protein-containing complex scaffold activity;2 iron, 2 sulfur cluster binding;4 iron, 4 sulfur cluster binding