Variant: NM_000540.3(RYR1):c.577T>A (p.Ser193Thr)

CA10642702

328993 (ClinVar)

Gene: RYR1

Condition: RYR1-related myopathy

Inheritance Mode: Autosomal dominant inheritance

UUID: 72d5c8c2-18b7-479a-b37a-6925d3c3c152

Approved on: 2024-08-27

Published on: 2025-01-03

HGVS expressions

NM_000540.3:c.577T>A
NM_000540.3(RYR1):c.577T>A (p.Ser193Thr)
NC_000019.10:g.38444623T>A
CM000681.2:g.38444623T>A
NC_000019.9:g.38935263T>A
CM000681.1:g.38935263T>A
NC_000019.8:g.43627103T>A
NG_008866.1:g.15924T>A
ENST00000599547.6:c.577T>A
ENST00000359596.8:c.577T>A
ENST00000355481.8:c.577T>A
ENST00000359596.7:c.577T>A
ENST00000360985.7:c.577T>A
NM_000540.2:c.577T>A
NM_001042723.1:c.577T>A
NM_001042723.2:c.577T>A

Uncertain Significance

• Met criteria codes: PP3

• Not Met criteria codes: PM2 BA1 BS1 BP4

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.577T>A variant in RYR1 is a missense variant predicted to cause substitution of serine by threonine at amino acid 193 (p.Ser193Thr). The highest population minor allele frequency in gnomAD v4.1 is 0.00002712 (32/1179992) in the European (non-Finnish) population (PM2_Supporting, BS1, and BA1 are not met). The REVEL score is 0.78, which is greater than the threshold of ≥ 0.7 set by the CM VCEP (PP3). In summary, this variant meets the criteria to be classified as uncertain significance for AD/AR RYR1-related myopathy based on the ACMG/AMP criteria applied, as specified by the ClinGen Congenital Myopathies VCEP: PP3. (ClinGen Congenital Myopathies VCEP specifications version 2; 08/27/2024)

Met criteria codes

• PP3: The REVEL score is 0.78, which is greater than the threshold of ≥ 0.7 set by the CM VCEP (PP3).

Not Met criteria codes

• PM2: The highest population minor allele frequency in gnomAD v4.1 is 0.00002712 (32/1179992) in the European (non-Finnish) population (PM2_Supporting, BS1, and BA1 are not met).
• BA1: The highest population minor allele frequency in gnomAD v4.1 is 0.00002712 (32/1179992) in the European (non-Finnish) population (PM2_Supporting, BS1, and BA1 are not met).
• BS1: The highest population minor allele frequency in gnomAD v4.1 is 0.00002712 (32/1179992) in the European (non-Finnish) population (PM2_Supporting, BS1, and BA1 are not met).
• BP4: The REVEL score is 0.78, which is greater than the threshold of ≥ 0.7 set by the CM VCEP (PP3).