Variant: NM_000540.3(RYR1):c.7025A>G (p.Asn2342Ser)

CA024665

133175 (ClinVar)

Gene: RYR1

Condition: RYR1-related myopathy

Inheritance Mode: Autosomal dominant inheritance

UUID: 087ae6c5-a8d4-4879-ae61-8038692c961b

Approved on: 2025-02-10

Published on: 2025-04-02

HGVS expressions

NM_000540.3:c.7025A>G
NM_000540.3(RYR1):c.7025A>G (p.Asn2342Ser)
NC_000019.10:g.38499241A>G
CM000681.2:g.38499241A>G
NC_000019.9:g.38989881A>G
CM000681.1:g.38989881A>G
NC_000019.8:g.43681721A>G
NG_008866.1:g.70542A>G
ENST00000599547.6:c.7025A>G
ENST00000359596.8:c.7025A>G
ENST00000355481.8:c.7025A>G
ENST00000359596.7:c.7025A>G
ENST00000360985.7:c.7022A>G
ENST00000594335.5:c.477A>G
NM_000540.2:c.7025A>G
NM_001042723.1:c.7025A>G
NM_001042723.2:c.7025A>G

Benign

• Met criteria codes: BS2 BS1

• Not Met criteria codes: PP3 PM3

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 2.0.0

Evidence submitted by expert panel

Congenital Myopathies VCEP

The c.7025A>G (NM_000540.3(RYR1):c.7025A>G (p.Asn2342Ser)) variant in RYR1 is a missense variant predicted to cause substitution of asparagine by serine at amino acid 2342 (p.Asn2342Ser). The highest MAF in gnomAD v4.1.0 is 0.001818 (2145/1180004 alleles) in the European (non-Finnish) population, which is greater than the ClinGen Congenital Myopathies VCEP threshold (≥0.000697) for BS1, and therefore meets this criterion (BS1). This variant has been observed in 3 homozygous individuals with no features of RYR1-related myopathy, a condition with full penetrance at an early age (BS2). The computational predictor REVEL gives a score of 0.639, which is neither above nor below the thresholds predicting a damaging or benign impact on RYR1 function. The variant is near the end of the exon, but the highest SpliceAI score is 0.04 for donor gain, and the other scores are 0.00, indicating no significant impact to splicing is predicted (no codes met). This variant was found in six probands from five families (two compound heterozygous and three heterozygous cases). However, none of these probands were scored due to the high population allele frequency, and, in specific cases, a potentially causative RYR1 variant on the same allele, a causative variant in another gene, or lack of phenotypic detail/specificity (no codes met; Synnovis Internal Data; PMIDs: 23826317, 31903994, 38982518). In summary, this variant meets the criteria to be classified as benign for RYR1-related myopathy (undetermined mode of inheritance) based on the ACMG/AMP criteria applied, as specified by the ClinGen Congenital Myopathy VCEP: (BS1, BS2; ClinGen Congenital Myopathies VCEP Specifications Version 2.0; 02/10/2025).

Met criteria codes

• BS2: This variant has been observed in 3 homozygous individuals with no features of RYR1-related myopathy, a condition with full penetrance at an early age (BS2). These individuals were present in gnomAD.
• BS1: The highest MAF in gnomAD v4.1.0 is 0.001818 (2145/1180004 alleles) in the European (non-Finnish) population, which is greater than the ClinGen Congenital Myopathies VCEP threshold (≥0.000697) for BS1, and therefore meets this criterion (BS1). Since the mode of inheritance is unclear and to thus be conservative, the autosomal recessive threshold frequency was used.

Not Met criteria codes

• PP3: The computational predictor REVEL gives a score of 0.639, which is neither above nor below the thresholds predicting a damaging or benign impact on RYR1 function. Variant is near the end of the exon, but the highest SpliceAI score is 0.04 for donor gain, and the other scores are 0.00, indicating no significant impact to splicing is predicted (no codes met).
• PM3: This variant was found in six probands from five families (two compound heterozygous and three heterozygous cases). However, none of these cases were scored due to the high population allele frequency, and, in specific cases, a potentially causative RYR1 variant on the same allele, a causative variant in another gene, or lack of phenotypic detail/specificity (Synnovis Internal Data; PMIDs: 23826317, 31903994, 38982518).