rs575780192
Variant summary
Our verdict is Uncertain significance. Variant got 0 ACMG points: 1P and 1B. PP2BP4
The NM_000540.3(RYR1):c.7204C>T(p.Arg2402Trp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000386 in 1,605,366 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign 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. R2402Q) 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 0 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
RYR1 | NM_000540.3 | c.7204C>T | p.Arg2402Trp | missense_variant | 44/106 | ENST00000359596.8 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
RYR1 | ENST00000359596.8 | c.7204C>T | p.Arg2402Trp | missense_variant | 44/106 | 5 | NM_000540.3 | A2 | |
RYR1 | ENST00000355481.8 | c.7204C>T | p.Arg2402Trp | missense_variant | 44/105 | 1 | P4 | ||
RYR1 | ENST00000594335.5 | c.658C>T | p.Arg220Trp | missense_variant, NMD_transcript_variant | 5/49 | 1 | |||
RYR1 | ENST00000599547.6 | c.7204C>T | p.Arg2402Trp | missense_variant, NMD_transcript_variant | 44/80 | 2 |
Frequencies
GnomAD3 genomes ? AF: 0.0000526 AC: 8AN: 152134Hom.: 0 Cov.: 32
GnomAD3 exomes AF: 0.000132 AC: 31AN: 235432Hom.: 0 AF XY: 0.000124 AC XY: 16AN XY: 128994
GnomAD4 exome AF: 0.0000372 AC: 54AN: 1453114Hom.: 1 Cov.: 34 AF XY: 0.0000443 AC XY: 32AN XY: 723076
GnomAD4 genome ? AF: 0.0000525 AC: 8AN: 152252Hom.: 0 Cov.: 32 AF XY: 0.0000537 AC XY: 4AN XY: 74454
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 01, 2023 | This missense variant replaces arginine with tryptophan at codon 2402 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). To our knowledge, functional studies have not been reported for this variant. This variant has not been reported in individuals affected with RYR1-related disorders in the literature. This variant has been identified in 34/266730 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 | clinical testing | Molecular Genetics, Royal Melbourne Hospital | Mar 30, 2023 | This sequence change is predicted to replace arginine with tryptophan at codon 2402 in exon 44 of the RYR1 protein (p.(Arg2402Trp)). The arginine residue is moderately conserved (100 vertebrates, UCSC), and is located in the RYR1 cytosolic shell. There is a large physicochemical difference between arginine and tryptophan. The variant is present in a large population cohort at a frequency of 0.01% (rs575780192, 34/266,730 alleles, 0 homozygotes in gnomAD v2.1), with a frequency of 0.1% in the east Asian population (25/19,482 alleles in gnomAD v2.1). The variant has been not been reported in RYR1-related disorders in the relevant medical literature, and has been reported as a variant of uncertain significance (ClinVar). Multiple lines of computational evidence predict a deleterious effect for the missense substitution (4/4 algorithms). Based on the classification scheme RMH Modified ACMG Guidelines v1.3.1, this variant is classified as a VARIANT OF UNCERTAIN SIGNIFICANCE. Following criteria are met: PP3. - |
not provided Uncertain:2
Uncertain significance, criteria provided, single submitter | clinical testing | GeneDx | May 24, 2022 | In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Has not been previously published as pathogenic or benign to our knowledge; This variant is associated with the following publications: (PMID: 20681998, 22473935, 16084090, 12668474) - |
Uncertain significance, criteria provided, single submitter | clinical testing | Mayo Clinic Laboratories, Mayo Clinic | Jun 22, 2023 | PP3 - |
not specified Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Genetic Services Laboratory, University of Chicago | Apr 10, 2015 | - - |
RYR1-related disorder Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Invitae | Jan 06, 2024 | This sequence change replaces arginine, which is basic and polar, with tryptophan, which is neutral and slightly polar, at codon 2402 of the RYR1 protein (p.Arg2402Trp). This variant is present in population databases (rs575780192, gnomAD 0.1%). 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: 212105). 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%. 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. - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at