rs193922846
Variant summary
Our verdict is Uncertain significance. Variant got 2 ACMG points: 2P and 0B. PM4
The NM_000540.3(RYR1):c.12960_12968delGCGGCGGCT(p.Arg4321_Leu4323del) variant causes a disruptive inframe deletion change. The variant allele was found at a frequency of 0.000103 in 1,005,090 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★★).
Frequency
Genomes: 𝑓 0.000095 ( 0 hom., cov: 31)
Exomes 𝑓: 0.00010 ( 0 hom. )
Consequence
RYR1
NM_000540.3 disruptive_inframe_deletion
NM_000540.3 disruptive_inframe_deletion
Scores
Not classified
Clinical Significance
Conservation
PhyloP100: 4.74
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 Uncertain_significance. Variant got 2 ACMG points.
PM4
Nonframeshift variant in NON repetitive region in NM_000540.3.
Transcripts
RefSeq
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Protein | Appris | UniProt |
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RYR1 | ENST00000359596.8 | c.12960_12968delGCGGCGGCT | p.Arg4321_Leu4323del | disruptive_inframe_deletion | 91/106 | 5 | NM_000540.3 | ENSP00000352608.2 | ||
RYR1 | ENST00000355481.8 | c.12945_12953delGCGGCGGCT | p.Arg4316_Leu4318del | disruptive_inframe_deletion | 90/105 | 1 | ENSP00000347667.3 | |||
RYR1 | ENST00000689936.1 | c.1350_1358delGCGGCGGCT | p.Arg451_Leu453del | disruptive_inframe_deletion | 8/22 | ENSP00000508999.2 | ||||
RYR1 | ENST00000688602.1 | n.1368_1376delGCGGCGGCT | non_coding_transcript_exon_variant | 9/23 | ENSP00000510767.2 |
Frequencies
GnomAD3 genomes AF: 0.0000954 AC: 14AN: 146752Hom.: 0 Cov.: 31
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GnomAD4 exome AF: 0.000105 AC: 90AN: 858338Hom.: 0 AF XY: 0.0000727 AC XY: 29AN XY: 398990
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GnomAD4 genome AF: 0.0000954 AC: 14AN: 146752Hom.: 0 Cov.: 31 AF XY: 0.0000420 AC XY: 3AN XY: 71388
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ClinVar
Significance: Uncertain significance
Submissions summary: Uncertain:5
Revision: criteria provided, multiple submitters, no conflicts
LINK: link
Submissions by phenotype
not provided Uncertain:3
Uncertain significance, criteria provided, single submitter | clinical testing | GeneDx | Jun 20, 2024 | Identified in a patient with dilated cardiomyopathy in the published literature and reported as a variant of uncertain significance (PMID: 32969603); In-frame deletion of 3 amino acids in a non-repeat region; In silico analysis indicates that this variant does not alter protein structure/function; This variant is associated with the following publications: (PMID: 32969603) - |
Uncertain significance, criteria provided, single submitter | clinical testing | Revvity Omics, Revvity | Jun 26, 2019 | - - |
Uncertain significance, criteria provided, single submitter | clinical testing | PreventionGenetics, part of Exact Sciences | Aug 05, 2015 | - - |
RYR1-related disorder Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Labcorp Genetics (formerly Invitae), Labcorp | Oct 28, 2022 | This variant, c.12960_12968del, results in the deletion of 3 amino acid(s) of the RYR1 protein (p.Arg4321_Leu4323del), but otherwise preserves the integrity of the reading frame. This variant is present in population databases (no rsID available, gnomAD 0.03%). This variant has been observed in individual(s) with nemaline myopathy by muscle biopsy (Invitae). ClinVar contains an entry for this variant (Variation ID: 544390). Experimental studies and prediction algorithms are not available or were not evaluated, and the functional significance of this variant is currently unknown. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. - |
Congenital myopathy with fiber type disproportion;C1840365:King Denborough syndrome;C1850674:Congenital multicore myopathy with external ophthalmoplegia;C2930980:Malignant hyperthermia, susceptibility to, 1;C5830701:Central core myopathy Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Fulgent Genetics, Fulgent Genetics | Jul 29, 2021 | - - |
Computational scores
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Find out detailed SpliceAI scores and Pangolin per-transcript scores at