rs200375946
Variant summary
Our verdict is Uncertain significance. Variant got 3 ACMG points: 3P and 0B. PP2PP3_Moderate
The NM_000540.3(RYR1):c.9800C>T(p.Pro3267Leu) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000638 in 1,613,928 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 (★★). Synonymous variant affecting the same amino acid position (i.e. P3267P) has been classified as Likely benign.
Frequency
Consequence
NM_000540.3 missense
Scores
Clinical Significance
Conservation
Genome browser will be placed here
ACMG classification
Verdict is Uncertain_significance. Variant got 3 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
RYR1 | NM_000540.3 | c.9800C>T | p.Pro3267Leu | missense_variant | 66/106 | ENST00000359596.8 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
RYR1 | ENST00000359596.8 | c.9800C>T | p.Pro3267Leu | missense_variant | 66/106 | 5 | NM_000540.3 | A2 | |
RYR1 | ENST00000355481.8 | c.9800C>T | p.Pro3267Leu | missense_variant | 66/105 | 1 | P4 | ||
RYR1 | ENST00000594335.5 | c.*543C>T | 3_prime_UTR_variant, NMD_transcript_variant | 26/49 | 1 | ||||
RYR1 | ENST00000599547.6 | c.*559C>T | 3_prime_UTR_variant, NMD_transcript_variant | 65/80 | 2 |
Frequencies
GnomAD3 genomes ? AF: 0.0000723 AC: 11AN: 152058Hom.: 0 Cov.: 31
GnomAD3 exomes AF: 0.0000519 AC: 13AN: 250490Hom.: 0 AF XY: 0.0000516 AC XY: 7AN XY: 135544
GnomAD4 exome AF: 0.0000629 AC: 92AN: 1461870Hom.: 0 Cov.: 34 AF XY: 0.0000660 AC XY: 48AN XY: 727240
GnomAD4 genome ? AF: 0.0000723 AC: 11AN: 152058Hom.: 0 Cov.: 31 AF XY: 0.0000673 AC XY: 5AN XY: 74266
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 proline with leucine at codon 3267 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 not been reported in individuals affected with RYR1-related disorders in the literature. This variant has been identified in 14/281804 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 | Oct 06, 2020 | - - |
Uncertain significance, criteria provided, single submitter | clinical testing | GeneDx | Jul 22, 2019 | In silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect; Has not been previously published as pathogenic or benign to our knowledge - |
RYR1-related disorder Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Invitae | Aug 30, 2021 | This sequence change replaces proline with leucine at codon 3267 of the RYR1 protein (p.Pro3267Leu). The proline residue is highly conserved and there is a moderate physicochemical difference between proline and leucine. This variant is present in population databases (rs200375946, ExAC 0.01%). 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: 224395). 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 | Jul 23, 2021 | - - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at