Evidence Repository
The ClinGen Evidence Repository is an FDA-recognized human genetic variant database containing expert-curated assertions regarding variants' pathogenicity and supporting evidence summaries. [Disclaimer]
  • Gene obtained from curated document aligns with the Allele Registry but not with ClinVar data
  • No CSPEC computed assertion could be determined for this classification!

Variant: NM_000540.3(RYR1):c.2677G>A (p.Gly893Ser)

CA024360

161362 (ClinVar)

Gene: RYR1
Condition: RYR1-related myopathy
Inheritance Mode: Autosomal dominant inheritance
Link to MONDO
UUID: 098c3599-4ed3-4bb0-93ac-3ead5a93be48
Approved on: 2024-08-27
Published on: 2025-01-03

HGVS expressions

NM_000540.3:c.2677G>A
NM_000540.3(RYR1):c.2677G>A (p.Gly893Ser)
NC_000019.10:g.38463522G>A
CM000681.2:g.38463522G>A
NC_000019.9:g.38954162G>A
CM000681.1:g.38954162G>A
NC_000019.8:g.43646002G>A
NG_008866.1:g.34823G>A
ENST00000599547.6:c.2677G>A
ENST00000359596.8:c.2677G>A
ENST00000355481.8:c.2677G>A
ENST00000359596.7:c.2677G>A
ENST00000360985.7:c.2677G>A
NM_000540.2:c.2677G>A
NM_001042723.1:c.2677G>A
NM_001042723.2:c.2677G>A
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Benign

Met criteria codes 1
BA1
Not Met criteria codes 3
PS4 PM2 BS1

Evidence Links 0

Expert Panel

Criteria Specification Information

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

Criteria Specification Approval History
Criteria Specifications for this VCEP
Evidence submitted by expert panel
Congenital Myopathies VCEP
The variant NM_000540.3:c.2677G>A in RYR1 is a missense variant predicted to cause substitution of glycine by serine at amino acid 893 (p.Gly893Ser). The highest population minor allele frequency in gnomAD v4.1.1 is 0.005439 (483/75052 alleles) for the African population, which is higher than the ClinGen congenital myopathy RYR1 threshold ( ≥ 0.0000486) for BA1, and therefore meets this criterion (BA1). This variant has been reported in one proband in the literature, who lacked a second allele and presented with type I muscle fiber predominance, proximal, axial, and facial weakness, limited upward gaze, and achilles tendon contracture. However, the father had the variant but was unaffected (PMID: 22473935). In summary, the variant meets criteria to be classified as benign for AD RYR1-related myopathy based on the ACMG/AMP criteria applied, as specified by the ClinGen Congenital Myopathies VCEP: BA1. (Congenital Myopathies VCEP specifications version 2; 08/27/2024).
Met criteria codes
BA1
The filtering allele frequency (the lower threshold of the 95% CI of 170/24210, 0 homozygotes) of the c.2677G>A variant in RYR1 is 0.005784 for African/African American chromosomes by gnomAD v4.1, which is higher than the ClinGen Congenital Myopathies VCEP threshold (≥0.0000486) for BA1, and therefore meets this criterion (BA1).
Not Met criteria codes
PS4
This variant has been reported in one proband in the literature (PMID: 22473935), however, the father of the proband had the variant but was unaffected.
PM2
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
Curation History
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