rs797045932
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Variant summary
Our verdict is Pathogenic. Variant got 16 ACMG points: 16P and 0B. PVS1PP5_Very_Strong
The NM_000540.3(RYR1):βc.2505delβ(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 (β β ). Variant results in nonsense mediated mRNA decay.
Frequency
Genomes: π 0.000026 ( 0 hom., cov: 33)
Exomes π: 0.000015 ( 0 hom. )
Consequence
RYR1
NM_000540.3 frameshift
NM_000540.3 frameshift
Scores
Not classified
Clinical Significance
Conservation
PhyloP100: 2.30
Genes affected
RYR1 (HGNC:10483): (ryanodine receptor 1) This gene encodes a ryanodine receptor found in skeletal muscle. The encoded protein functions as a calcium release channel in the sarcoplasmic reticulum but also serves to connect the sarcoplasmic reticulum and transverse tubule. Mutations in this gene are associated with malignant hyperthermia susceptibility, central core disease, and minicore myopathy with external ophthalmoplegia. Alternatively spliced transcripts encoding different isoforms have been described. [provided by RefSeq, Jul 2008]
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ACMG classification
Classification made for transcript
Verdict is Pathogenic. Variant got 16 ACMG points.
PVS1
Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.
PP5
Variant 19-38460514-CG-C is Pathogenic according to our data. Variant chr19-38460514-CG-C is described in ClinVar as [Likely_pathogenic]. Clinvar id is 212099.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr19-38460514-CG-C is described in Lovd as [Pathogenic].
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | Protein | UniProt |
---|---|---|---|---|---|---|---|---|
RYR1 | NM_000540.3 | c.2505del | p.Pro836LeufsTer48 | frameshift_variant | 20/106 | ENST00000359596.8 | NP_000531.2 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Protein | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|---|
RYR1 | ENST00000359596.8 | c.2505del | p.Pro836LeufsTer48 | frameshift_variant | 20/106 | 5 | NM_000540.3 | ENSP00000352608 | A2 | |
RYR1 | ENST00000355481.8 | c.2505del | p.Pro836LeufsTer48 | frameshift_variant | 20/105 | 1 | ENSP00000347667 | P4 | ||
RYR1 | ENST00000599547.6 | c.2505del | p.Pro836LeufsTer48 | frameshift_variant, NMD_transcript_variant | 20/80 | 2 | ENSP00000471601 |
Frequencies
GnomAD3 genomes AF: 0.0000263 AC: 4AN: 152236Hom.: 0 Cov.: 33
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GnomAD3 exomes AF: 0.0000119 AC: 3AN: 251204Hom.: 0 AF XY: 0.00000736 AC XY: 1AN XY: 135812
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GnomAD4 exome AF: 0.0000150 AC: 22AN: 1461806Hom.: 0 Cov.: 32 AF XY: 0.0000165 AC XY: 12AN XY: 727206
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GnomAD4 genome AF: 0.0000263 AC: 4AN: 152236Hom.: 0 Cov.: 33 AF XY: 0.0000134 AC XY: 1AN XY: 74380
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ClinVar
Significance: Pathogenic/Likely pathogenic
Submissions summary: Pathogenic:7
Revision: criteria provided, multiple submitters, no conflicts
LINK: link
Submissions by phenotype
not provided Pathogenic:3
Pathogenic, criteria provided, single submitter | clinical testing | Eurofins Ntd Llc (ga) | Aug 24, 2015 | - - |
Pathogenic, criteria provided, single submitter | clinical testing | Revvity Omics, Revvity | Oct 02, 2020 | - - |
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) - |
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 - |
Congenital multicore myopathy with external ophthalmoplegia;C5830701:Central core myopathy 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]. - |
RYR1-related disorder Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Labcorp Genetics (formerly Invitae), Labcorp | 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. - |
Myopathy Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Genetic Services Laboratory, University of Chicago | Jul 17, 2015 | - - |
Computational scores
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Details are displayed if max score is > 0.2
Find out detailed SpliceAI scores and Pangolin per-transcript scores at