Rhabdomyolysis and metabolic muscle disorders

Gene: CASQ1

Green List (high evidence)

Comment on list classification: There is sufficient evidence available (>20 unrelated cases and functional studies) for this gene to be promoted to GREEN at the next GMS update. This gene is currently not included on any GMS panels despite sufficient evidence to support the gene-disease association. Phenotypes displayed by affected individuals such as muscle weakness and fatigue, exercise-induced myalgia and hyperCKaemia align with rhabdomyolysis panels. Inclusion on this panel would also ensure inclusion on the R381 super panel, as suggested by the GMS expert group.

Created: 14 Oct 2025, 11:10 a.m. | Last Modified: 14 Oct 2025, 11:14 a.m.

Panel Version: 5.12

Copied and amended relevant reviews from panel R82, where inclusion of this gene was disagreed due to lack of clinically significant variants identified in >1000 screened patients but addition to another component panel of R381 was suggested:


PMID:26136523 reported 10 cases from three families with the founder missense variant, pAsp244Gly and they all had benign vacuolar myopathy, muscle weaknesses and hyperCKaemia. All patients reported adult onset. 1 proband reported lower limb hypertrophy with normal EMG results. 6 patients had muscle biopsy, with minimal fibre size variation, and a few central nuclei.

PMID:28895244 reported the identification of three novel variants (p.Asp44Asn, p.Gly103Asp & p.Ile385Thr) in four cases with with tubular aggregate myopathy. They had fatigue and diffuse exercise-induced myalgia and the patient with p.Ile385Thr variant also had proximal muscle weakness.

PMID:29039140 reported two unrelated families with heterozygous variants (family1: p.Asn54Tyr; family 2: p.Gly103Asp). Family 1 presented between early 20s and mid-40s with a slowly progressive muscle weakness mainly involving proximal muscles in the lower limbs and family 2 presented with post-exercise myalgia in the lower limbs in early 50s.

PMID:30258016 reported 22 cases from 12 families with heterozygous variants in CASQ1. 21 of these cases shared the founder variant (p.Asp244Gly) and one had p.Gly103Asp variant. These patients usually had adult-onset exercise intolerance, elevated CK and myalgias and later developed slowly progressive proximal weakness with quadriceps atrophy and scapular winging. Three patients presented subclinical cardiac abnormalities and four patients had pelvic girdle weakness.

PMID:34908252 reported a case with a heterozygous missense variant p.Asp44Asn, who presented with exercise‐induced muscle spasms since childhood.

PMID:36514469 reported a Chinese patient who presented with slowly progressive upper limb weakness, predominantly affecting distal muscles and was identified with heterozygous variant p.Val256Met in CASQ1.

This gene has been associated with relevant phenotypes in OMIM (MIM #616231), but not in Gene2Phenotype.
Sources: Literature

Created: 14 Oct 2025, 11:05 a.m.

Mode of inheritance
MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown

Phenotypes
Myopathy, vacuolar, with CASQ1 aggregates, OMIM:616231

Publications

• 26136523
• 28895244
• 29039140
• 30258016
• 34908252
• 36514469