rs201358408
Variant summary
Our verdict is Uncertain significance. Variant got 2 ACMG points: 2P and 0B. PP2PP3
The NM_000540.3(RYR1):c.10492C>G(p.Arg3498Gly) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000644 in 1,613,828 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 Uncertain significance (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R3498H) has been classified as Uncertain significance.
Frequency
Consequence
NM_000540.3 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Uncertain_significance. Variant got 2 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
RYR1 | NM_000540.3 | c.10492C>G | p.Arg3498Gly | missense_variant | 71/106 | ENST00000359596.8 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
RYR1 | ENST00000359596.8 | c.10492C>G | p.Arg3498Gly | missense_variant | 71/106 | 5 | NM_000540.3 | A2 | |
RYR1 | ENST00000355481.8 | c.10477C>G | p.Arg3493Gly | missense_variant | 70/105 | 1 | P4 | ||
RYR1 | ENST00000594335.5 | c.*1220C>G | 3_prime_UTR_variant, NMD_transcript_variant | 30/49 | 1 | ||||
RYR1 | ENST00000599547.6 | c.*1251C>G | 3_prime_UTR_variant, NMD_transcript_variant | 70/80 | 2 |
Frequencies
GnomAD3 genomes ? AF: 0.0000592 AC: 9AN: 151980Hom.: 0 Cov.: 30
GnomAD3 exomes AF: 0.0000279 AC: 7AN: 251258Hom.: 0 AF XY: 0.00000736 AC XY: 1AN XY: 135850
GnomAD4 exome AF: 0.0000650 AC: 95AN: 1461848Hom.: 0 Cov.: 32 AF XY: 0.0000564 AC XY: 41AN XY: 727228
GnomAD4 genome ? AF: 0.0000592 AC: 9AN: 151980Hom.: 0 Cov.: 30 AF XY: 0.0000539 AC XY: 4AN XY: 74200
ClinVar
Submissions by phenotype
Malignant hyperthermia, susceptibility to, 1 Uncertain:2
Uncertain significance, criteria provided, single submitter | clinical testing | All of Us Research Program, National Institutes of Health | Dec 18, 2023 | This missense variant replaces arginine with glycine at codon 3498 of the RYR1 protein. Computational prediction is inconclusive regarding the impact of this variant on protein structure and function (internally defined REVEL score threshold 0.5 < inconclusive < 0.7, PMID: 27666373). To our knowledge, functional studies have not been reported for this variant. This variant has been reported in a family affected with malignant hyperthermia susceptibility, but the variant did not co-segregate with disease (PMID: 24195946). This variant has been identified in 8/282550 chromosomes in the general population by the Genome Aggregation Database (gnomAD). The available evidence is insufficient to determine the role of this variant in disease conclusively. Therefore, this variant is classified as a Variant of Uncertain Significance. - |
Uncertain significance, criteria provided, single submitter | research | Biesecker Lab/Clinical Genomics Section, National Institutes of Health | Jul 01, 2013 | - - |
not provided Uncertain:2
Uncertain significance, criteria provided, single submitter | clinical testing | Revvity Omics, Revvity | May 07, 2021 | - - |
Uncertain significance, criteria provided, single submitter | clinical testing | GeneDx | Nov 30, 2020 | Not observed at a significant frequency in large population cohorts (Lek et al., 2016); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Identified via exome sequencing in a volunteer not ascertained for malignant hyperthermia susceptibility (MHS) who was found to have a three generation family history of MHS; however, the variant did not segregate with the phenotype in the family (Gonsalves et al., 2013); This variant is associated with the following publications: (PMID: 24195946) - |
RYR1-related disorder Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Invitae | May 12, 2022 | This sequence change replaces arginine, which is basic and polar, with glycine, which is neutral and non-polar, at codon 3498 of the RYR1 protein (p.Arg3498Gly). This variant is present in population databases (rs201358408, gnomAD 0.008%). This missense change has been observed in individual(s) with malignant hyperthermia (PMID: 24195946). ClinVar contains an entry for this variant (Variation ID: 224398). Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Benign"; Align-GVGD: "Class C0"). 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;C0751951:Central core myopathy;C1840365:King Denborough syndrome;C1850674:Congenital multicore myopathy with external ophthalmoplegia;C2930980:Malignant hyperthermia, susceptibility to, 1 Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Fulgent Genetics, Fulgent Genetics | Aug 02, 2021 | - - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at