Variant: NM_000540.3(RYR1):c.8310+1G>T

CA405677313

1253809 (ClinVar)

Gene: RYR1

Condition: RYR1-related myopathy

Inheritance Mode: Autosomal recessive inheritance

UUID: 847fc8d2-7c8a-4ccd-9c7a-f48721b307ce

Approved on: 2024-08-07

Published on: 2024-10-01

HGVS expressions

NM_000540.3:c.8310+1G>T
NM_000540.3(RYR1):c.8310+1G>T
NC_000019.10:g.38505082G>T
CM000681.2:g.38505082G>T
NC_000019.9:g.38995722G>T
CM000681.1:g.38995722G>T
NC_000019.8:g.43687562G>T
NG_008866.1:g.76383G>T
ENST00000599547.6:c.8310+1G>T
ENST00000359596.8:c.8310+1G>T
ENST00000355481.8:c.8310+1G>T
ENST00000359596.7:c.8310+1G>T
ENST00000360985.7:c.8307+1G>T
ENST00000594335.5:c.1762+1G>T
NM_000540.2:c.8310+1G>T
NM_001042723.1:c.8310+1G>T
NM_001042723.2:c.8310+1G>T

Pathogenic

• Met criteria codes: PP4 PM3_Strong PVS1

• Not Met criteria codes: BA1 PM2 BS1

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

Evidence submitted by expert panel

Congenital Myopathies VCEP

The c.8310+1G>T (NM_000540.3(RYR1):c.8310+1G>T) variant in RYR1 occurs within the canonical splice donor site (+1) of intron 52. It is predicted to cause skipping of biologically-relevant exon 52, resulting in a frameshift leading to nonsense mediated decay in a gene in which loss-of-function is an established disease mechanism (PVS1). The highest population minor allele frequency in gnomAD v4.1 is 0.00001336 (1/74870 alleles) in the African/African American population (PM2_Supporting, BS1, and BA1 are not met). This variant has been detected in at least 2 individuals with autosomal recessive RYR1-related myopathy. For both of those individuals, they were compound heterozygous for the variant and a pathogenic/likely pathogenic variant and both of those were confirmed in trans by parental testing (PM3_strong; SCV002012482; GeneDx and HudsonAlpha Institute for Biotechnology Internal Data; PMID: 34930662). At least one patient with this variant displayed neonatal hypotonia, and reduced mobility of facial muscles and extremities, which is highly specific for autosomal recessive RYR1-related myopathies (PP4; SCV002012482; GeneDx and HudsonAlpha Institute for Biotechnology Internal Data; PMID: 34930662). In summary, this variant meets the criteria to be classified as pathogenic for autosomal recessive RYR1-related myopathies based on the ACMG/AMP criteria applied, as specified by the ClinGen Congenital Myopathies VCEP: PVS1, PM3_Strong, PP4 (Congenital Myopathies VCEP specifications Version 1; 8/7/2024).

Met criteria codes

• PP4: At least one patient with this variant displayed neonatal hypotonia and reduced mobility of muscles, which is highly specific for autosomal recessive RYR1-related myopathies. (PP4; GeneDx and HudsonAlpha Institute of Biotechnology Internal Data).
• PM3_Strong: This variant has been detected in at least 2 individuals with autosomal recessive RYR1-related myopathy. For both of those individuals, they were compound heterozygous for the variant and a pathogenic/likely pathogenic variant and both of those were confirmed in trans by parental testing (NM_000540.3:c.10348-6C>G; GeneDx and AlphaHudson Institute for Biotechnology; PM3_strong).
• PVS1: The c.8310+1G>T(NM_000540.3(RYR1):c.8310+1G>T) variant in RYR1 occurs within the canonical splice donor/acceptor site (+1) of intron 52. It is predicted to cause skipping of biologically-relevant exon 52, resulting in a frameshift leading to nonsense mediated decay in a gene in which loss-of-function is an established disease mechanism (PVS1).

Not Met criteria codes

• BA1: The highest population minor allele frequency in gnomAD v4.1 is 0.00001336 (1/74870 alleles) in the African/African American population. (PM2_Supporting, BS1, and BA1 are not met)
• PM2: The highest population minor allele frequency in gnomAD v4.1 is 0.00001336 (1/74870 alleles) in the African/African American population. (PM2_Supporting, BS1, and BA1 are not met)
• BS1: The highest population minor allele frequency in gnomAD v4.1 is 0.00001336 (1/74870 alleles) in the African/African American population. (PM2_Supporting, BS1, and BA1 are not met)