rs377178986
Variant summary
Our verdict is Pathogenic. Variant got 16 ACMG points: 16P and 0B. PVS1PP5_Very_Strong
The NM_000540.3(RYR1):c.11763C>A(p.Tyr3921Ter) variant causes a stop gained change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000458 in 1,614,116 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★★). Variant results in nonsense mediated mRNA decay.
Frequency
Consequence
NM_000540.3 stop_gained
Scores
Clinical Significance
Conservation
Genome browser will be placed here
ACMG classification
Verdict is Pathogenic. Variant got 16 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
RYR1 | NM_000540.3 | c.11763C>A | p.Tyr3921Ter | stop_gained | 85/106 | ENST00000359596.8 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
RYR1 | ENST00000359596.8 | c.11763C>A | p.Tyr3921Ter | stop_gained | 85/106 | 5 | NM_000540.3 | A2 |
Frequencies
GnomAD3 genomes ? AF: 0.0000328 AC: 5AN: 152238Hom.: 0 Cov.: 32
GnomAD3 exomes AF: 0.0000239 AC: 6AN: 251492Hom.: 0 AF XY: 0.0000221 AC XY: 3AN XY: 135920
GnomAD4 exome AF: 0.0000472 AC: 69AN: 1461878Hom.: 0 Cov.: 32 AF XY: 0.0000454 AC XY: 33AN XY: 727242
GnomAD4 genome ? AF: 0.0000328 AC: 5AN: 152238Hom.: 0 Cov.: 32 AF XY: 0.0000269 AC XY: 2AN XY: 74374
ClinVar
Submissions by phenotype
not provided Pathogenic:3
Pathogenic, criteria provided, single submitter | clinical testing | PreventionGenetics, part of Exact Sciences | Oct 30, 2019 | - - |
Pathogenic, criteria provided, single submitter | clinical testing | GeneDx | Feb 24, 2023 | Nonsense variant predicted to result in protein truncation or nonsense mediated decay in a gene for which loss-of-function is a known mechanism of disease; Not observed at a significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 25637381, 28818389, 32721234, 25683120, 22473935, 23553484) - |
Likely pathogenic, criteria provided, single submitter | clinical testing | Revvity Omics, Revvity | Nov 11, 2021 | - - |
Inborn genetic diseases Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Ambry Genetics | Dec 14, 2017 | - - |
Malignant hyperthermia, susceptibility to, 1 Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Mendelics | May 27, 2022 | - - |
Congenital myopathy with fiber type disproportion Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Women's Health and Genetics/Laboratory Corporation of America, LabCorp | Jul 08, 2021 | Variant summary: RYR1 c.11763C>A (p.Tyr3921X) results in a premature termination codon, experimentally demonstrated to lead to absence of transcription (and therefore of the protein) (Zhou_2006, Klein_2012) due to nonsense mediated decay, which is a commonly known mechanism for disease. The variant allele was found at a frequency of 2.4e-05 in 251492 control chromosomes (gnomAD). c.11763C>A has been reported in the literature in individuals affected with autosomal recessive RYR1-related myopathy (e.g. Klein_2012, Amburgey_2013). These data indicate that the variant is likely to be associated with disease. Three ClinVar submitters (evaluation after 2014) cite the variant as pathogenic and one ClinVar submitter (evaluation after 2014) cites it as benign. Based on the evidence outlined above, the variant was classified as pathogenic. - |
RYR1-Related Disorders Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Invitae | Jul 28, 2023 | This sequence change creates a premature translational stop signal (p.Tyr3921*) in the RYR1 gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in RYR1 are known to be pathogenic (PMID: 23919265, 25960145, 28818389, 30611313). This variant is present in population databases (rs377178986, gnomAD 0.008%). This premature translational stop signal has been observed in individuals with autosomal recessive RYR1-related conditions (PMID: 22473935, 28818389). ClinVar contains an entry for this variant (Variation ID: 161361). For these reasons, this variant has been classified as Pathogenic. - |
Congenital myopathy with fiber type disproportion;C0751951:Central core myopathy;C1840365:King Denborough syndrome;C1850674:Congenital multicore myopathy with external ophthalmoplegia;C2930980:Malignant hyperthermia, susceptibility to, 1 Pathogenic:1
Likely pathogenic, criteria provided, single submitter | clinical testing | Fulgent Genetics, Fulgent Genetics | Apr 11, 2022 | - - |
Congenital myopathy Benign:1
Likely benign, no assertion criteria provided | research | CSER _CC_NCGL, University of Washington | Jun 01, 2014 | - - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at