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.10048C>A (p.Arg3350=)

CA052256

256386 (ClinVar)

Gene: RYR1
Condition: RYR1-related myopathy
Inheritance Mode: Undetermined mode of inheritance
Link to MONDO
UUID: dad9b609-08a8-48fa-8cda-329873908808
Approved on: 2024-08-07
Published on: 2024-10-02

HGVS expressions

NM_000540.3:c.10048C>A
NM_000540.3(RYR1):c.10048C>A (p.Arg3350=)
NC_000019.10:g.38519243C>A
CM000681.2:g.38519243C>A
NC_000019.9:g.39009883C>A
CM000681.1:g.39009883C>A
NC_000019.8:g.43701723C>A
NG_008866.1:g.90544C>A
ENST00000599547.6:c.9987C>A
ENST00000359596.8:c.10048C>A
ENST00000355481.8:c.10048C>A
ENST00000359596.7:c.10048C>A
ENST00000360985.7:c.10045C>A
ENST00000594335.5:c.3450C>A
ENST00000599547.5:c.855C>A
NM_000540.2:c.10048C>A
NM_001042723.1:c.10048C>A
NM_001042723.2:c.10048C>A
More

Likely Benign

Met criteria codes 3
BS1 BP7 BP4
Not Met criteria codes 10
PM5 PM4 PM2 BS3 PVS1 BS2 BP3 PS1 PS3 BA1

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 1.0.0

Criteria Specification Approval History
Criteria Specifications for this VCEP
Evidence submitted by expert panel
Congenital Myopathies VCEP
The NM_000540.3:c.10048C>A variant in the RYR1 gene is a synonymous variant (p.Arg3350=). The filtering allele frequency (the lower threshold of the 95% CI of 195/1180010) of the c.10048C>A variant in RYR1 is 0.0001406 for European (non-Finnish) chromosomes by gnomAD v4.1, which is higher than the ClinGen Congenital Myopathies VCEP threshold (0.0001406) for BS1, and therefore meets this criterion (BS1). This silent variant is not predicted to impact splicing by SpliceAI. In addition, it occurs at a nucleotide that is poorly conserved as shown by the UCSC Genome Browser (BP4, BP7). In summary, the variant meets the criteria to be classified as likely benign for RYR1-related myopathy. ACMG/AMP criteria met, as specified by the ClinGen Congenital Myopathies VCEP: BS1, BP4, BP7 (ClinGen Congenital Myopathies VCEP specifications version 1; 8/7/2024).
Met criteria codes
BS1
The filtering allele frequency (the lower threshold of the 95% CI of 195/1180010) of the c.10048C>A variant in RYR1 is 0.0001406 for European (non-Finnish) chromosomes by gnomAD v4.1, which is higher than the ClinGen Congenital Myopathies VCEP threshold (0.0001406) for BS1, and therefore meets this criterion (BS1).
BP7
SpliceAI gives a score of 0.01 for acceptor loss/gain
BP4
It occurs at a nucleotide that is poorly conserved as shown by the UCSC Genome Browser
Not Met criteria codes
PM5
No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
PM4
No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
PM2
No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
BS3
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 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
PS1
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
BA1
No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
Curation History
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