Variant: NM_001042723.2:c.14536C>G

CA405687674

Gene: RYR1

Condition: RYR1-related myopathy

Inheritance Mode: Autosomal dominant inheritance

UUID: b86ff299-3d2f-43f2-a966-5dbc556e308b

Approved on: 2025-09-15

Published on: 2025-09-19

HGVS expressions

NM_001042723.2:c.14536C>G
NC_000019.10:g.38580409C>G
CM000681.2:g.38580409C>G
NC_000019.9:g.39071049C>G
CM000681.1:g.39071049C>G
NC_000019.8:g.43762889C>G
NG_008866.1:g.151710C>G
ENST00000593677.2:c.1487C>G
ENST00000688602.1:c.2884C>G
ENST00000689936.1:c.2856C>G
ENST00000359596.8:c.14551C>G
ENST00000355481.8:c.14536C>G
ENST00000359596.7:c.14551C>G
ENST00000360985.7:c.14533C>G
NM_000540.2:c.14551C>G
NM_001042723.1:c.14536C>G
NM_000540.3:c.14551C>G

Likely Pathogenic

• Met criteria codes: PP3 PM1 PS4_Moderate PM2_Supporting

Expert Panel

Congenital Myopathies VCEP

Criteria Specification Information

Criteria Specification: ClinGen Congenital Myopathies Expert Panel Specifications to the ACMG/AMP Variant Interpretation Guidelines for RYR1 Version 2.0.0

Evidence submitted by expert panel

Congenital Myopathies VCEP

The NM_000540.3:c.14551C>G variant in RYR1 is a missense variant predicted to cause substitution of leucine by valine at amino acid 4851 (p. Leu4851Val). This variant is absent from gnomAD v4.1 (PM2_Supporting). The computational predictor REVEL gives a score of 0.828, which is above the threshold of 0.7, evidence that correlates with impact to RYR1 function (PP3). This variant resides within the pore/transmembrane region, amino acids 4800-4950, of RYR1 that is defined as a critical functional domain by the ClinGen Congenital Myopathies VCEP (PM1). This variant has been reported in 1 proband meeting presence of central cores in muscle biopsy and characteristic muscle imaging. The patient had delayed motor milestones and was seen by a neurologist at ~70yo for progressive proximal muscle weakness and normal CK. The biopsy showed “Dusty central cores” and Type 1 fiber predominance. Muscle MRI imaging is compatible with RYR1-related disease, including sparing of rectus femoris muscle (0.5pts, PS4_Moderate; Internal VCEP contributors). In summary, this variant meets the criteria to be classified as likely pathogenic for autosomal dominant RYR1-related myopathy based on the ACMG/AMP criteria applied, as specified by the ClinGen Congenital Myopathies VCEP: PS4_Moderate, PM1, PM2_Supporting, PP3. (ClinGen Congenital Myopathies VCEP specifications version 2.0.0; September 15th, 2025).

Met criteria codes

• PP3: The computational predictor REVEL gives a score of 0.828, which is above the threshold of 0.7, evidence that correlates with impact to RYR1 function (PP3).
• PM1: This variant resides within the pore/transmembrane region, amino acids 4800-4950, of RYR1 that is defined as a critical functional domain by the ClinGen Congenital Myopathies VCEP (PM1).
• PS4_Moderate: This variant has been reported in 1 proband meeting presence of central cores in muscle biopsy and characteristic muscle imaging. The patient had delayed motor milestones and was seen by a neurologist at ~70yo for progressive proximal muscle weakness and normal CK. The biopsy showed “Dusty central cores” and Type 1 fiber predominance. Muscle MRI imaging is compatible with RYR1-related disease, including sparing of rectus femoris muscle (0.5pts, PS4_Moderate; Internal VCEP contributors).
• PM2_Supporting: This variant is absent from gnomAD v4.1 (PM2_Supporting).