Evidence Repository - Clinical Genome Resources

The ClinGen Evidence Repository is an FDA-recognized human genetic variant database containing expert-curated assertions regarding variants' pathogenicity and supporting evidence summaries. [Disclaimer]

Variant: NM_000540.3(RYR1):c.958-11del

Curation Version - 1.0
Curation History
JSON LD for Version 1.0

CA073846

256586 (ClinVar)

Gene: RYR1

Condition: RYR1-related myopathy

Inheritance Mode: Undetermined mode of inheritance

Link to MONDO

UUID: c0aafc82-df17-4d08-bbfb-45363db05cc8

Approved on: 2024-08-07

Published on: 2024-10-02

HGVS expressions

NM_000540.3:c.958-11del

NM_000540.3(RYR1):c.958-11del

NC_000019.10:g.38448638del

CM000681.2:g.38448638del

NC_000019.9:g.38939278del

CM000681.1:g.38939278del

NC_000019.8:g.43631118del

NG_008866.1:g.19939del

ENST00000599547.6:c.958-11del

ENST00000359596.8:c.958-11del

ENST00000355481.8:c.958-11del

ENST00000359596.7:c.958-11del

ENST00000360985.7:c.958-11del

NM_000540.2:c.958-11del

NM_001042723.1:c.958-11del

NM_001042723.2:c.958-11del

Likely Benign

BS1 BP7 BP4

PM2 BA1

Evidence Links 0

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 1.0.0

Criteria Specification Approval History

Criteria Specifications for this VCEP

Evidence submitted by expert panel

Congenital Myopathies VCEP

The c.985-11del (NM_000540.3(RYR1):c.958-11del) variant in RYR1 is an intronic variant, located in intron 10 and 11 bases upstream of exon 11. The filtering allele frequency (the lower threshold of the 95% CI of 1684/64032 with 32 homozygous observations) of the c.958-11del variant in RYR1 is 0.0001110 for European (non-Finnish) chromosomes by gnomAD v4.1, which is higher than the ClinGen Congenital Myopathies VCEP threshold (≥0.0000006) for BS1, and therefore meets this criterion (BS1). The computational splicing predictor SpliceAI gives a score of 0.05 for acceptor gain, suggesting that the variant has no impact on splicing. In addition, it occurs at a nucleotide that is not conserved as shown by UCSC genome browser (BP4/BP7). In summary, this variant meets the criteria to be classified as likely benign for RYR1-related myopathies, based on the ACMG/AMP criteria applied, as specified by the ClinGen Congenital Myopathies VCEP: BS1, BP4, BP7 (Congenital Myopathies VCEP Specifications Version 1; 8/7/2024).

BS1

The filtering allele frequency (the lower threshold of the 95% CI of 1684/64032) of the c.958-11del variant in RYR1 is 0.0001110 for European (non-Finnish) chromosomes by gnomAD v4.1, which is higher than the ClinGen Congenital Myopathies VCEP threshold (≥0.0000006) for BS1, and therefore meets this criterion (BS1).

BP7

The computational splicing predictor SpliceAI gives a score of 0.05 for acceptor gain suggesting that the variant has no impact on splicing (BP7). Predicted score for acceptor gain is 0.05, and score is 0.00 for acceptor loss, donor loss, and donor gain.

BP4

The computational splicing predictor SpliceAI gives a score of 0.05 for acceptor gain suggesting that the variant has no impact on splicing (BP4). Predicted score for acceptor gain is 0.05, and score is 0.00 for acceptor loss, donor loss, and donor gain.

PM2

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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