rs193922849
Variant summary
Our verdict is Likely benign. Variant got -5 ACMG points: 3P and 8B. PP2PP3_ModerateBP6_Very_Strong
The NM_000540.3(RYR1):c.12406C>A(p.Arg4136Ser) variant causes a missense change. The variant allele was found at a frequency of 0.0000105 in 1,613,992 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 benign (★★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R4136H) has been classified as Uncertain significance.
Frequency
Consequence
NM_000540.3 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Likely_benign. Variant got -5 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
RYR1 | NM_000540.3 | c.12406C>A | p.Arg4136Ser | missense_variant | 90/106 | ENST00000359596.8 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
RYR1 | ENST00000359596.8 | c.12406C>A | p.Arg4136Ser | missense_variant | 90/106 | 5 | NM_000540.3 | A2 |
Frequencies
GnomAD3 genomes ? AF: 0.00000657 AC: 1AN: 152194Hom.: 0 Cov.: 32
GnomAD3 exomes AF: 0.0000239 AC: 6AN: 251116Hom.: 0 AF XY: 0.0000221 AC XY: 3AN XY: 135778
GnomAD4 exome AF: 0.0000109 AC: 16AN: 1461798Hom.: 0 Cov.: 34 AF XY: 0.00000688 AC XY: 5AN XY: 727212
GnomAD4 genome ? AF: 0.00000657 AC: 1AN: 152194Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0AN XY: 74350
ClinVar
Submissions by phenotype
not provided Uncertain:1Other:1
not provided, no classification provided | literature only | Leiden Muscular Dystrophy (RYR1) | - | - - |
Uncertain significance, criteria provided, single submitter | clinical testing | PreventionGenetics, part of Exact Sciences | Apr 27, 2016 | - - |
RYR1-Related Disorders Pathogenic:1
Likely pathogenic, criteria provided, single submitter | clinical testing | Invitae | Jan 22, 2024 | This sequence change replaces arginine, which is basic and polar, with serine, which is neutral and polar, at codon 4136 of the RYR1 protein (p.Arg4136Ser). This variant is present in population databases (rs193922849, gnomAD 0.004%). This missense change has been observed in individual(s) with malignant hyperthermia susceptibility (PMID: 12208234). ClinVar contains an entry for this variant (Variation ID: 133037). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) has been performed at Invitae for this missense variant, however the output from this modeling did not meet the statistical confidence thresholds required to predict the impact of this variant on RYR1 protein function. In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic. - |
Malignant hyperthermia of anesthesia Benign:1
Likely benign, reviewed by expert panel | curation | ClinGen Malignant Hyperthermia Susceptibility Variant Curation Expert Panel, ClinGen | Mar 16, 2021 | This pathogenicity assessment is relevant only for malignant hyperthermia susceptibility (MHS) inherited in an autosomal dominant pattern. Variants in RYR1 can also cause other myopathies inherited in an autosomal dominant pattern or in an autosomal recessive pattern. Some of these disorders may predispose individuals to malignant hyperthermia. RYR1 variants may also contribute to a malignant hyperthermia reaction in combination with other genetic and non-genetic factors and the clinician needs to consider such factors in making management decisions. This sequence variant predicts a substitution of arginine with serine at codon 4136 of the RYR1 protein, p.(Arg4136Ser). The maximum allele frequency for this variant among the six major gnomAD populations is NFE: 0.0000349, a frequency consistent with pathogenicity for MHS. This variant has been reported in an individual with myopathy that was MHS, this variant was also present in the father who was MHN by IVCT, PS4 not met, BS2_Moderate (PMID: 12208234). No functional studies were identified for this variant. This variant does not reside in a hotspot for pathogenic variants that contribute to MHS. A REVEL score of 0.783 supports neither a pathogenic nor a benign status for this variant. Based on using Bayes to combine criteria this variant is assessed as Likely Benign, (PMID: 29300386). Criteria implemented: BS2_Moderate. - |
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 Benign:1
Likely benign, criteria provided, single submitter | clinical testing | Fulgent Genetics, Fulgent Genetics | Sep 16, 2021 | - - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at