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.1077T>C (p.Ala359=)

Curation Version - 1.0
Curation History
JSON LD for Version 1.0

CA023860

93243 (ClinVar)

Gene: RYR1

Condition: RYR1-related myopathy

Inheritance Mode: Undetermined mode of inheritance

Link to MONDO

UUID: 9afce82c-2e70-4ada-b016-d424b8f60629

Approved on: 2024-08-07

Published on: 2024-10-02

HGVS expressions

NM_000540.3:c.1077T>C

NM_000540.3(RYR1):c.1077T>C (p.Ala359=)

NC_000019.10:g.38448768T>C

CM000681.2:g.38448768T>C

NC_000019.9:g.38939408T>C

CM000681.1:g.38939408T>C

NC_000019.8:g.43631248T>C

NG_008866.1:g.20069T>C

ENST00000599547.6:c.1077T>C

ENST00000359596.8:c.1077T>C

ENST00000355481.8:c.1077T>C

ENST00000359596.7:c.1077T>C

ENST00000360985.7:c.1077T>C

NM_000540.2:c.1077T>C

NM_001042723.1:c.1077T>C

NM_001042723.2:c.1077T>C

Benign

BP4 BP7 BA1

BS1 PM2

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 variant NM_000540.3:c.1077T>C in RYR1 is a synonymous (silent) variant (p.Ala359=). The filtering allele frequency (the lower threshold of the 95% CI of 19809/19952, 9835 homozygotes) of the c.1077T>C variant in RYR1 is 0.9807 for East Asian chromosomes by gnomAD v4.1, which is higher than the ClinGen Congenital Myopathies VCEP threshold (≥0.00697) for BA1, and therefore meets this criterion (BA1). The c.1077T>C (p.Ala359=) variant is a synonymous (silent) variant that is not predicted by SpliceAI to impact splicing. In addition, it occurs at a nucleotide that is not conserved as shown by UCSC Genome Browser (BP4, BP7). In summary, the variant meets criteria to be classified as benign. ACMG/AMP criteria met, as specified by the congenital myopathies VCEP: BA1, BP4, BP7 (ClinGen Congenital Myopathies VCEP specifications version 1; 8/7/2024).

BP4

SpliceAI predicted no impact on splicing, meeting BP4/BP7 criteria.

BP7

SpliceAI predicted no impact on splicing, meeting BP4/BP7 criteria.

BA1

The filtering allele frequency (the lower threshold of the 95% CI of 19809/19952, 9835 homozygotes) of the c.1077T>C variant in RYR1 is 0.9807 for East Asian chromosomes by gnomAD v4.1, which is higher than the ClinGen Congenital Myopathies VCEP threshold (≥0.00697) for BA1, and therefore meets this criterion (BA1).

BS1

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

Curation History

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