19-38577948-C-T
Variant summary
Our verdict is Uncertain significance. Variant got 4 ACMG points: 4P and 0B. PM1PP2PP3
The NM_000540.3(RYR1):c.14203C>T(p.Arg4735Trp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000285 in 1,613,962 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. R4735Q) 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 4 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
RYR1 | NM_000540.3 | c.14203C>T | p.Arg4735Trp | missense_variant | 98/106 | ENST00000359596.8 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
RYR1 | ENST00000359596.8 | c.14203C>T | p.Arg4735Trp | missense_variant | 98/106 | 5 | NM_000540.3 | A2 |
Frequencies
GnomAD3 genomes ? AF: 0.0000526 AC: 8AN: 152090Hom.: 0 Cov.: 32
GnomAD3 exomes AF: 0.0000358 AC: 9AN: 251392Hom.: 0 AF XY: 0.0000368 AC XY: 5AN XY: 135898
GnomAD4 exome AF: 0.0000260 AC: 38AN: 1461872Hom.: 0 Cov.: 32 AF XY: 0.0000234 AC XY: 17AN XY: 727236
GnomAD4 genome ? AF: 0.0000526 AC: 8AN: 152090Hom.: 0 Cov.: 32 AF XY: 0.0000673 AC XY: 5AN XY: 74294
ClinVar
Submissions by phenotype
not provided Uncertain:3
Uncertain significance, criteria provided, single submitter | clinical testing | Eurofins Ntd Llc (ga) | Dec 13, 2016 | - - |
Uncertain significance, criteria provided, single submitter | clinical testing | Revvity Omics, Revvity | Nov 11, 2019 | - - |
Uncertain significance, criteria provided, single submitter | clinical testing | Athena Diagnostics | Sep 17, 2020 | This observation is not an independent occurrence and has been identified in the same individual by RCIGM, the other laboratory participating in the GEMINI study. - |
not specified Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Women's Health and Genetics/Laboratory Corporation of America, LabCorp | Jan 23, 2019 | Variant summary: RYR1 c.14203C>T (p.Arg4735Trp) results in a non-conservative amino acid change in the encoded protein sequence. Four of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 4e-05 in 277056 control chromosomes (gnomAD). This frequency is not significantly higher than expected for a pathogenic variant in RYR1 causing Malignant Hyperthermia Susceptibility (4e-05 vs 8.8e-05), allowing no conclusion about variant significance. c.14203C>T has been reported in the literature in homozygous form, in case report, describing a newborn who had severe hypotonia, similar to some other patients with mutations at different loci in RYR1, however the patient also had cerebral atrophy and dysfunction, which is unusual for RYR1-related disorders (Gilfert 2016). This report therefore does not provide unequivocal conclusions about association of the variant with Malignant Hyperthermia Susceptibility (MHS). To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. However, a study for a different missense change affecting the same amino acid (Arg4735Gln), showed pathological contractures after caffeine and halothane application, where the in vitro contracture tests were performed on a muscle biopsy specimen taken from a heterozygote patient with a history of clinical MH and a histology positive for central cores (Klingler 2014). In addition, some neighboring missense changes (p.Y4733D, p.G4734E, p.R4737Q, p.R4737W), have been reported in patients with malignant hyperthermia (HGMD). These data support the functional significance of this region. Two clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation, and classified the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as VUS-possibly pathogenic. - |
Inborn genetic diseases Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Ambry Genetics | Apr 07, 2016 | - - |
RYR1-related disorder Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Invitae | Jan 24, 2024 | This sequence change replaces arginine, which is basic and polar, with tryptophan, which is neutral and slightly polar, at codon 4735 of the RYR1 protein (p.Arg4735Trp). This variant is present in population databases (rs766887342, gnomAD 0.02%). 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: 199248). 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) performed at Invitae indicates that this missense variant is expected to disrupt RYR1 protein function with a positive predictive value of 95%. This variant disrupts the p.Arg4735 amino acid residue in RYR1. Other variant(s) that disrupt this residue have been observed in individuals with RYR1-related conditions (PMID: 24433488), which suggests that this may be a clinically significant amino acid residue. 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. - |
Malignant hyperthermia, susceptibility to, 1 Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | All of Us Research Program, National Institutes of Health | Nov 20, 2023 | This missense variant replaces arginine with tryptophan at codon 4735 of the RYR1 protein. Computational prediction suggests that this variant may have deleterious impact on protein structure and function (internally defined REVEL score threshold >= 0.7, PMID: 27666373). Although functional studies have not been reported for this variant, it occurs in the C-terminal region of the RYR1 protein (a.a. 4,631-4,991) that is considered to be a hotspot for pathogenic variants that may contribute to malignant hyperthermia susceptibility as well as other phenotype(s) (PMID: 21118704). This variant has not been reported in individuals affected with autosomal dominant malignant hyperthermia in the literature, although it is associated with other phenotype(s) (ClinVar variation ID: 199248). This variant has been identified in 11/282720 chromosomes in the general population by the Genome Aggregation Database (gnomAD). Due to insufficient evidence, this variant is classified as a Variant of Uncertain Significance for autosomal dominant malignant hyperthermia. - |
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 | Sep 07, 2021 | - - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at