Table 1.
Clinical and molecular findings in the investigated patients.
| Patient/sex | Age range (years) | Phenotype | RYR1 genetic variant | Protein alteration/domain | Functional regions | Validation | Variant classification (ACMG) | Note |
|---|---|---|---|---|---|---|---|---|
| 1/F | 40-50 |
• Clinical severity: moderate • Congenital hip dysplasia • Delayed motor milestones • Myopathic face • Mild hypotonia • Proximal weakness starting in childhood • Severe scoliosis • Fatigability • CK: 138 U/L • EMG: moderate myogenic pattern |
c.14678G>A het (Ex 102) |
p.Arg4893Gln Pore |
CCD hotspot 3 | Family segregation: dominant transmission [12, 16–18] | Likely pathogenic: PP3-PM2-PM5-PP2 | Presence of an additional variant in cis in RYR1 (c.8327C>T p.Ser2776Phe het Domain RYR3-4) linked to MH [31, 32] |
| 2/M | 50–60 |
• Clinical severity: moderate • Late onset (50 yrs) • Head drop • Mild hypophonia • Proximal weakness • CK: 522 U/L • EMG: myogenic-neurogenic pattern |
c.7600G>A het (Ex 47) |
p.Ala2534Thr Bsol |
Critical region for skeletal-type E-C coupling (1635–2636) | NA | VUS: PM2-PP2 | New variant (this report) |
| 3/F | <10 |
• Clinical severity: severe • Congenital arthrogryposis • Scoliosis • Delayed motor milestones • Proximal weakness • Wheelchair dependent • Restrictive respiratory pattern • CK: normal (10792 U/L at birth) EMG: myogenic pattern |
c.131G>A hom (Ex2) |
p.Arg44His NTD-A |
MH/CCD hotspot 1 | Family segregation: recessive transmission [12, 13] | Likely pathogenic: PP3-PM2-PM5-PM1-PP2-PS4 | |
| 4/F | <10 |
• Clinical severity: severe • Delayed motor milestones • Pectus excavatum • Ophthalmoparesis • Moderate proximal weakness • Recurrent lung infections • CK: normal • EMG: myogenic pattern |
c.325C>T het (Ex4) c.13622del het (Ex 93) |
p.Arg109Trp NTD-A p.Phe4541Serfs*10 Link-pVSD |
MH/CCD hotspot 1 Important region for activation/inactivation (aa 4300–4850) |
Expression studies in HEK cells [14, 15] Loss of function |
Pathogenic: PM3-PP3-PM2-PM5-PP2-PS3-PP1-PP5 Likely pathogenic-PVS1-PM2 |
New variant (this report) |
Clinical phenotype, genetic and protein variants of patients. RYR1 RefSeq: NM_000540.3 (NP_000531.2).
ACMG American College of Medical Genetics and Genomics, CK Creatine Kinase, EMG electromyography, E-C coupling Excitation-Contraction coupling.