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.9472+1G>A

CA073621

451330 (ClinVar)

Gene: RYR1
Condition: RYR1-related myopathy
Inheritance Mode: Autosomal recessive inheritance
Link to MONDO
UUID: 40b5dff4-41b9-4491-8dca-04b7bf118f30
Approved on: 2024-08-07
Published on: 2024-10-02

HGVS expressions

NM_000540.3:c.9472+1G>A
NM_000540.3(RYR1):c.9472+1G>A
NC_000019.10:g.38512484G>A
CM000681.2:g.38512484G>A
NC_000019.9:g.39003124G>A
CM000681.1:g.39003124G>A
NC_000019.8:g.43694964G>A
NG_008866.1:g.83785G>A
ENST00000599547.6:c.9411+1G>A
ENST00000359596.8:c.9472+1G>A
ENST00000355481.8:c.9472+1G>A
ENST00000359596.7:c.9472+1G>A
ENST00000360985.7:c.9469+1G>A
ENST00000594335.5:c.2874+1G>A
ENST00000599547.5:c.279+1G>A
NM_000540.2:c.9472+1G>A
NM_001042723.1:c.9472+1G>A
NM_001042723.2:c.9472+1G>A
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Pathogenic

Met criteria codes 3
PM2_Supporting PP4 PVS1
Not Met criteria codes 1
PM3

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 c.9472+1G>A (NM_000540.3(RYR1):c.9472+1G>A) variant in RYR1 occurs within the canonical splice donor site (+ 1) of intron 63. It is predicted to cause skipping of biologically-relevant-exon 63, resulting in a frameshift leading to nonsense mediated decay in a gene in which loss-of-function is an established disease mechanism (PVS1). The total grpmax in gnomAD v4.1.0 is 0.00000068 or 0.000068% in the European (non-Finnish) population (3/1179972) (PM2_supporting). This variant was found in a compound heterozygous state with a variant of uncertain significance (p.Arg282Trp (c.844C>T)) in an affected proband (phase unknown). The proband with the variants displayed susceptibility to heat hyperthermia, single type 1 congenital neuromuscular disease, and micronuclear myopathy with extraocular muscle paraplegia, features highly specific for autosomal recessive RYR1-related myopathy (PP4; 10.3760/cma.j.cn511374-20200729-00564). In summary, this variant meets the criteria to be classified as pathogenic for autosomal recessive RYR1-related myopathy based on the ACMG/AMP criteria applied, as specified by the ClinGen Congenital Myopathies VCEP: PVS1, PM2_Supporting, PP4 (Congenital Myopathies VCEP specifications Version 1: 8/7/2024).
Met criteria codes
PM2_Supporting
The total grpmax in gnomAD v4.1.0 is 0.00000068 or 0.000068% in the European (non-Finnish) population (3/1179972) (PM2_supporting).
PP4
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).
PVS1
The c.9472+1 G>A (NM_000540.3(RYR1):c.9472+1G>A) variant in RYR1 occurs within the canonical splice donor site (+ 1) of intron 63. It is predicted to cause skipping of biologically-relevant-exon 63, resulting in a frameshift leading to nonsense mediated decay in a gene in which loss-of- function is an established disease mechanism (PVS1). This canonical splice site variant causes out of frame exon-skipping of exon 63, leading to a premature stop codon. This exon is present in biologically relevant transcripts. It truncates nearly 2/5 of the protein.
Not Met criteria codes
PM3
This variant was reported along with another RYR-1 variant (p.Arg282Trp) (phase unspecified). The p.Arg282Trp variant has conflicting classifications in ClinVar (1 likely pathogenic, 2 uncertain significance classifications). The patient was a fetus analyzed at 13 weeks of pregnancy. The fetus had bilateral pleural effusion, ascites, and subcutaneous edema thickening. The pregnancy was terminated. This was a whole-exome sequencing investigation of fetuses suspected to have defects (DOI: 10.22541/au.159534877.71223144).
Curation History
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