rs369182023
Variant summary
Our verdict is Uncertain significance. Variant got 1 ACMG points: 1P and 0B. PP2
The NM_000540.3(RYR1):c.2812G>A(p.Val938Met) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000345 in 1,592,672 control chromosomes in the GnomAD database, with no homozygous occurrence. 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. V938L) 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 1 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
RYR1 | NM_000540.3 | c.2812G>A | p.Val938Met | missense_variant | 23/106 | ENST00000359596.8 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
RYR1 | ENST00000359596.8 | c.2812G>A | p.Val938Met | missense_variant | 23/106 | 5 | NM_000540.3 | A2 | |
RYR1 | ENST00000355481.8 | c.2812G>A | p.Val938Met | missense_variant | 23/105 | 1 | P4 | ||
RYR1 | ENST00000599547.6 | c.2812G>A | p.Val938Met | missense_variant, NMD_transcript_variant | 23/80 | 2 |
Frequencies
GnomAD3 genomes ? AF: 0.0000788 AC: 12AN: 152196Hom.: 0 Cov.: 31
GnomAD3 exomes AF: 0.0000692 AC: 15AN: 216786Hom.: 0 AF XY: 0.0000690 AC XY: 8AN XY: 115934
GnomAD4 exome AF: 0.0000299 AC: 43AN: 1440476Hom.: 0 Cov.: 31 AF XY: 0.0000406 AC XY: 29AN XY: 714184
GnomAD4 genome ? AF: 0.0000788 AC: 12AN: 152196Hom.: 0 Cov.: 31 AF XY: 0.0000942 AC XY: 7AN XY: 74346
ClinVar
Submissions by phenotype
Malignant hyperthermia, susceptibility to, 1 Uncertain:1
Uncertain significance, criteria provided, single submitter | research | Biesecker Lab/Clinical Genomics Section, National Institutes of Health | Jul 01, 2013 | - - |
RYR1-related disorder Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Invitae | Sep 13, 2022 | This sequence change replaces valine, which is neutral and non-polar, with methionine, which is neutral and non-polar, at codon 938 of the RYR1 protein (p.Val938Met). This variant is present in population databases (rs369182023, gnomAD 0.04%). 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: 224376). 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 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 26, 2021 | - - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at