Rhabdomyolysis and metabolic muscle disorders

Gene: ISCU

Green List (high evidence)

Comment on mode of inheritance: There is sufficient evidence available (two unrelated cases and functional evidence from patient cells and yeast) for the association of monoallelic variants with metabolic myopathy. Hence, this gene can be promoted to green rating in the next GMS update.

Created: 9 Oct 2026, 10:27 a.m. | Last Modified: 9 Oct 2026, 10:27 a.m.

Panel Version: 6.12

Biallelic ISCU variants are associated with myopathy with lactic acidosis in OMIM (MIM #255125) and the record was last accessed on 09 October 2026. Biallelic variants are associated with mitochondrial disease (MONDO:0044970) with 'Definitive' rating by the Mitochondrial diseases GCEP in ClinGen.

PMID:29079705 (2017) reported an Italian male patient that presented in childhood with ptosis, severe muscle weakness and exercise intolerance. His disease was slowly progressive, with partial recovery between episodes. This patient was identified with a novel de novo dominant variant in ISCU gene (p.Gly96Val). Histochemical and biochemical analyses on muscle biopsy showed multiple defects affecting mitochondrial respiratory chain complexes. Patient fibroblasts showed normal levels of ISCU protein and a few variably affected Fe-S cluster-dependent enzymes. Yeast studies confirmed both pathogenicity and dominance of the identified missense variant.

PMID:40529812 (2025) reported the identification of a novel heterozygous variant c.399del (p.Val134Ter) in the ISCU gene in an adult female patient with progressive muscle weakness. This variant was also found in a few family members, who present signs of myopathy. Functional studies in yeast not only confirmed the pathogenetic effect of the variant, but also supported its dominant inheritance.

Monoallelic variants are not yet associated with any phenotypes in OMIM or ClinGen.

Created: 9 Oct 2026, 10:24 a.m. | Last Modified: 9 Oct 2026, 10:24 a.m.

Panel Version: 6.9

Mode of inheritance
BOTH monoallelic and biallelic, autosomal or pseudoautosomal

Phenotypes
Myopathy with lactic acidosis, hereditary, OMIM:255125; hereditary myopathy with lactic acidosis due to ISCU deficiency, MONDO:0009706

Publications

• 29079705
• 40529812

The mode of inheritance of this gene has been updated to 'BIALLELIC, autosomal or pseudoautosomal' following NHS Genomic Medicine Service approval.

Created: 2 May 2024, 11:15 a.m. | Last Modified: 2 May 2024, 11:15 a.m.

Panel Version: 4.3

Added 'for-review' tag as the MOI has changed since previous sign-off of this panel (version 1.34) and requires review by the Specialist Test Group.

Created: 21 Oct 2020, 4:27 p.m. | Last Modified: 21 Oct 2020, 4:50 p.m.

Panel Version: 1.43

Mode of inheritance
BIALLELIC, autosomal or pseudoautosomal

The to_be_confirmed_NHSE tag has been added, as further NHSE review is required.

Created: 15 Mar 2022, 3:36 p.m. | Last Modified: 15 Mar 2022, 3:36 p.m.

Panel Version: 1.78

Comment on mode of inheritance: Comment on mode of inheritance: PMID 29079705 reports a novel de novo dominant variant missense p.G97V variant has been reported and therefore this may represent a specific mechanism of action. Further evidence is needed to determine which (if any) other monoallelic variants will cause disease beyond mitochondrial myopathy, which justifies the mode of inheritance recorded.

Created: 23 Jun 2020, 2:10 p.m. | Last Modified: 23 Jun 2020, 2:10 p.m.

Panel Version: 1.42

Comment when marking as ready: Associated with phenotype in OMIM, not in G2P / DD. At least two variants reported, numerous reports of IVS5, +382G>C (g.7044G>C), with evidence provided that this variant results in abnormal splicing, a frameshift and termination. In vitro evidence for reduced active gene product

Created: 5 Dec 2016, 3:26 p.m.