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 label mismatch: RYR1 vs undefined
  • 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.10204T>G (p.Cys3402Gly)

CA023822

42098 (ClinVar)

Gene: RYR1
Condition: RYR1-related myopathy
Inheritance Mode: Autosomal recessive inheritance
Link to MONDO
UUID: 7b52166b-8d2a-4c9f-b5e9-f39c4eca57b6
Approved on: 2025-02-10
Published on: 2025-04-03

HGVS expressions

NM_000540.3:c.10204T>G
NM_000540.3(RYR1):c.10204T>G (p.Cys3402Gly)
NC_000019.10:g.38519399T>G
CM000681.2:g.38519399T>G
NC_000019.9:g.39010039T>G
CM000681.1:g.39010039T>G
NC_000019.8:g.43701879T>G
NG_008866.1:g.90700T>G
ENST00000599547.6:c.10143T>G
ENST00000359596.8:c.10204T>G
ENST00000355481.8:c.10204T>G
ENST00000359596.7:c.10204T>G
ENST00000360985.7:c.10201T>G
ENST00000594335.5:c.3606T>G
ENST00000599547.5:c.1011T>G
NM_000540.2:c.10204T>G
NM_001042723.1:c.10204T>G
NM_001042723.2:c.10204T>G
More

Pathogenic

Met criteria codes 3
PP1 PP3 PM3_Very Strong
Not Met criteria codes 23
PS3 PS2 PS4 PS1 PP4 PP2 BA1 PM6 PM2 PM5 PM1 PM4 PVS1 BS2 BS3 BS4 BS1 BP5 BP7 BP2 BP4 BP1 BP3

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 NM_000540.3:c.10204T>G (p.Cys3402Gly) variant in RYR1 is a missense variant predicted to cause a substitution of cysteine by glycine at amino acid 3402. The computational predictor REVEL gives a score of 0.851, which is above the threshold for predicting a damaging effect on RYR1 variants (PP3). The highest population minor allele frequency in gnomAD v4.1.0 is 0.00006 (7/117872 alleles) in European (non-Finnish) population, which is higher than the ClinGen Congenital Myopathies VCEP threshold (≤0.00000697) for PM2_Supporting and lower than ClinGen Congenital Myopathies VCEP threshold (≥0.000697) for BS1, therefore no population criteria can be applied. The variant has been reported in trans with a second pathogenic RYR1 variant or a rare variant of uncertain significance in RYR1 in 10 probands with clinical features of congenital myopathy (PMID: 20583297; Synnovis internal data SCV001468505.1; Invitae internal data SCV000659742.9) (PM3_Very Strong). The variant along with another pathogenic variant in trans was identified in two siblings with congenital myopathy suggesting cosegregation (Invitae internal data) (PP1). In summary, this variant meets the criteria to be classified as pathogenic for autosomal recessive RYR1-related myopathy based on the ACMG/AMP criteria applied as specified by the ClinGen Congenital Myopathy VCEP: PM3_Very Strong, PP1, PP3 (ClinGen Congenital Myopathies VCEP Specifications 2.0.0; 2/10/2025).
Met criteria codes
PP1
Labcorp Genetics reported 2 affected siblings found to have this variant confirmed in trans with another RYR1 variant by parental testing.
PP3
The REVEL score is over 0.7
PM3_Very Strong
The variant has been reported in trans with a second pathogenic RYR1 variant or a rare variant of uncertain significance in RYR1 in 10 probands with clinical features of congenital myopathy (PMID: 20583297; Synnovis internal data SCV001468505.1; Invitae internal data SCV000659742.9). Total points per the PM3 chart from laboratory data and Patient 2 of PMID: 20583297 using submissions from Clinvar is 7 points. Even when very conservatively calling L/LP variants in ClinVar without VCEP classifications as VUSs, the proband counting would be 4 points which is also over PM3_Very Strong threshold.
Not Met criteria codes
PS3
No functional data
PS2
The variant was inherited from heterozygous parent in PMID:20583297
PS4
Not applicable for autosomal recessive RYR1
PS1
No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
PP4
The proband in PMID: 20583297 only meets the ophthalmoplegia specification outlined in the VCEP's PP4 criteria specifications, therefore, PP4 is not met.
PP2
RYR1 is not constrained for missense variants
BA1
Variant is present in 7 heterozygotes in gnomAD and 2 heterozygotes in ExAC and has an allele frequency of 0.00003 which is less than the BA1 frequency threshold
PM6
The variant was inherited from heterozygous parent in PMID:20583297
PM2
Variant is present in 7 heterozygotes in gnomAD and 2 heterozygotes in ExAC and has an allele frequency of 0.00003 which is above the PM2 frequency threshold for both autosomal recessive and autosomal dominant variants
PM5
No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
PM1
The variant is not within the pore/transmembrane region of RYR1 critical for protein function (amino acids 4800-4950)
PM4
No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
PVS1
No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
BS2
No homozygotes noted in population databases nor in affected patients.
BS3
No functional data
BS4
No available segregation data
BS1
Variant is present in 7 heterozygotes in gnomAD and 2 heterozygotes in ExAC and has an allele frequency of 0.00003 which is less than the BS1 frequency threshold (≥0.000697) for both autosomal recessive but above the ≥0.00000486 threshold for autosomal dominant.
BP5
PMID: 20583297 had negative genetic testing for DM1 and myotubular myopathy.
BP7
No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
BP2
Heterozygous parent for other variant was unaffected.
BP4
The REVEL score is over 0.7
BP1
No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
BP3
No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
Curation History
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