Variant: NM_000540.3(RYR1):c.13949T>C (p.Leu4650Pro)

CA024091

65961 (ClinVar)

Gene: RYR1

Condition: RYR1-related myopathy

Inheritance Mode: Autosomal dominant inheritance

UUID: c007e9f7-f2ea-4f49-93aa-7177998da4ee

Approved on: 2024-08-27

Published on: 2025-01-03

HGVS expressions

NM_000540.3:c.13949T>C
NM_000540.3(RYR1):c.13949T>C (p.Leu4650Pro)
NC_000019.10:g.38572221T>C
CM000681.2:g.38572221T>C
NC_000019.9:g.39062861T>C
CM000681.1:g.39062861T>C
NC_000019.8:g.43754701T>C
NG_008866.1:g.143522T>C
ENST00000593677.2:c.885T>C
ENST00000688602.1:c.2282T>C
ENST00000689936.1:c.2254T>C
ENST00000359596.8:c.13949T>C
ENST00000355481.8:c.13934T>C
ENST00000359596.7:c.13949T>C
ENST00000360985.7:c.13931T>C
ENST00000593677.1:c.409T>C
NM_000540.2:c.13949T>C
NM_001042723.1:c.13934T>C
NM_001042723.2:c.13934T>C

Uncertain Significance

• Met criteria codes: PM2_Supporting PP4 PP3 PM3

• Not Met criteria codes: BA1 BP4 BS1 PM1 PM5 PS3 PS1

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 c.13949T>C variant in RYR1 is a missense variant predicted to cause substitution of leucine by proline at amino acid 4650 (p.Leu4650Pro). This variant is absent from gnomAD v4.1.1 (PM2_Supporting). The REVEL computational prediction analysis tool gives a score of 0.805, which is above the threshold of 0.7, evidence that correlates with impact to RYR1 function (PP3). This variant has been detected in two individuals with central core disease (CCD). Of those individuals, both were compound heterozygous for the variant and a VUS and both of those were confirmed in trans by parental testing (RYR1 p.Lys4724Gln, PMID: 12937085, PMID: 30611313, ClinVar Variation ID: 65957) (PM3). At least one patient with this variant displayed Type I fiber predominance, unique large eccentric cores, few necrotic/regenerative fibers, and connective tissue increase, which is highly specific for RYR1-related myopathy (PP4, PMID: 12937085). In summary, the variant meets the criteria to be classified as uncertain significance for autosomal recessive RYR1-related myopathy. ACMG/AMP criteria met, as specified by the ClinGen Congenital Myopathies VCEP: PM2_Supporting, PP3, PM3, PP4 (ClinGen Congenital Myopathies VCEP specifications version 2; 08/27/2024).

Met criteria codes

• PM2_Supporting: This variant is absent from gnomAD v4.1 (PM2_Supporting).
• PP4: At least one patient with this variant displayed Type I fiber predominance, unique large eccentric cores, few necrotic/regenerative fibers, and connective tissue increase, which is highly specific for RYR1-related myopathy (PP4, PMID: 12937085)
• PP3: The computational predictor REVEL gives a score of 0.805, which is above the threshold of 0.7, evidence that correlates with impact to RYR1 function (PP3).
• PM3: This variant has been detected in two individuals with central core disease (CCD). Of those individuals, both were compound heterozygous for the variant and a VUS and both of those were confirmed in trans by parental testing (RYR1 p.Lys4724Gln, PM3 points: 1, PMID: 12937085, PMID: 30611313, ClinVar Variation ID: 65957) (PM3).

Not Met criteria codes

• BA1: No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
• BP4: No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
• BS1: No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
• PM1: No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
• PM5: No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
• PS3: No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
• PS1: No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline