rs797045932
Variant summary
Our verdict is Pathogenic. Variant got 16 ACMG points: 16P and 0B. PVS1PP5_Very_Strong
The NM_000540.3(RYR1):c.2505del(p.Pro836LeufsTer48) variant causes a frameshift change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000161 in 1,614,042 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Likely pathogenic (★★). Synonymous variant affecting the same amino acid position (i.e. R834R) has been classified as Likely benign. Variant results in nonsense mediated mRNA decay.
Frequency
Consequence
NM_000540.3 frameshift
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.2505del | p.Pro836LeufsTer48 | frameshift_variant | 20/106 | ENST00000359596.8 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
RYR1 | ENST00000359596.8 | c.2505del | p.Pro836LeufsTer48 | frameshift_variant | 20/106 | 5 | NM_000540.3 | A2 | |
RYR1 | ENST00000355481.8 | c.2505del | p.Pro836LeufsTer48 | frameshift_variant | 20/105 | 1 | P4 | ||
RYR1 | ENST00000599547.6 | c.2505del | p.Pro836LeufsTer48 | frameshift_variant, NMD_transcript_variant | 20/80 | 2 |
Frequencies
GnomAD3 genomes ? AF: 0.0000263 AC: 4AN: 152236Hom.: 0 Cov.: 33
GnomAD3 exomes AF: 0.0000119 AC: 3AN: 251204Hom.: 0 AF XY: 0.00000736 AC XY: 1AN XY: 135812
GnomAD4 exome AF: 0.0000150 AC: 22AN: 1461806Hom.: 0 Cov.: 32 AF XY: 0.0000165 AC XY: 12AN XY: 727206
GnomAD4 genome ? AF: 0.0000263 AC: 4AN: 152236Hom.: 0 Cov.: 33 AF XY: 0.0000134 AC XY: 1AN XY: 74380
ClinVar
Submissions by phenotype
not provided Pathogenic:3
Pathogenic, criteria provided, single submitter | clinical testing | Eurofins Ntd Llc (ga) | Aug 24, 2015 | - - |
Likely pathogenic, criteria provided, single submitter | clinical testing | GeneDx | Apr 19, 2022 | Frameshift 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); Identified in an individual from a large study of pediatric patients undergoing clinical exome sequencing. Clinical information on this individual was not provided (Miller et al., 2020); This variant is associated with the following publications: (PMID: 34691145, 32371413) - |
Pathogenic, criteria provided, single submitter | clinical testing | Revvity Omics, Revvity | Oct 02, 2020 | - - |
Congenital multicore myopathy with external ophthalmoplegia Pathogenic:1
Likely pathogenic, criteria provided, single submitter | clinical testing | Laboratory of Medical Genetics, National & Kapodistrian University of Athens | Apr 26, 2023 | PM2, PM3, PP2, PP3, PP5 - |
RYR1-related disorder Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Invitae | Jan 24, 2024 | This sequence change creates a premature translational stop signal (p.Pro836Leufs*48) 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 (rs797045932, gnomAD 0.01%). This variant has not been reported in the literature in individuals affected with RYR1-related conditions. ClinVar contains an entry for this variant (Variation ID: 212099). For these reasons, this variant has been classified as Pathogenic. - |
Central core myopathy;C1850674:Congenital multicore myopathy with external ophthalmoplegia Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Institute for Genomic Medicine (IGM) Clinical Laboratory, Nationwide Children's Hospital | May 10, 2017 | [ACMG/AMP: PVS1, PM2, PP5] This alteration is a null variant in a gene where LOF is a known mechanism of disease [PVS1], is absent from or rarely observed in large-scale population databases [PM2], was reported as a pathogenic/likely pathogenic alteration by a reputable source (ClinVar or other correspondence from a clinical testing laboratory) [PP5]. - |
Myopathy Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Genetic Services Laboratory, University of Chicago | Jul 17, 2015 | - - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at