rs756331568
Variant summary
Our verdict is Uncertain significance. Variant got 5 ACMG points: 5P and 0B. PP2PP3_Strong
The NM_000540.3(RYR1):c.9571G>A(p.Gly3191Arg) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000155 in 1,549,190 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 Conflicting classifications of pathogenicity (no stars). Synonymous variant affecting the same amino acid position (i.e. G3191G) has been classified as Likely benign.
Frequency
Consequence
NM_000540.3 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Uncertain_significance. Variant got 5 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
RYR1 | NM_000540.3 | c.9571G>A | p.Gly3191Arg | missense_variant | 65/106 | ENST00000359596.8 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
RYR1 | ENST00000359596.8 | c.9571G>A | p.Gly3191Arg | missense_variant | 65/106 | 5 | NM_000540.3 | A2 | |
RYR1 | ENST00000355481.8 | c.9571G>A | p.Gly3191Arg | missense_variant | 65/105 | 1 | P4 | ||
RYR1 | ENST00000594335.5 | c.*314G>A | 3_prime_UTR_variant, NMD_transcript_variant | 25/49 | 1 | ||||
RYR1 | ENST00000599547.6 | c.*330G>A | 3_prime_UTR_variant, NMD_transcript_variant | 64/80 | 2 |
Frequencies
GnomAD3 genomes AF: 0.0000131 AC: 2AN: 152246Hom.: 0 Cov.: 32
GnomAD3 exomes AF: 0.00000652 AC: 1AN: 153276Hom.: 0 AF XY: 0.00 AC XY: 0AN XY: 81478
GnomAD4 exome AF: 0.0000157 AC: 22AN: 1396944Hom.: 0 Cov.: 31 AF XY: 0.0000160 AC XY: 11AN XY: 688960
GnomAD4 genome AF: 0.0000131 AC: 2AN: 152246Hom.: 0 Cov.: 32 AF XY: 0.0000134 AC XY: 1AN XY: 74378
ClinVar
Submissions by phenotype
not provided Pathogenic:1Uncertain:1
Pathogenic, criteria provided, single submitter | clinical testing | GeneDx | Aug 02, 2022 | In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Not observed at significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 12668474, 35693006) - |
Uncertain significance, criteria provided, single submitter | clinical testing | PreventionGenetics, part of Exact Sciences | Oct 28, 2013 | - - |
RYR1-related disorder Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Invitae | Nov 13, 2023 | This sequence change replaces glycine, which is neutral and non-polar, with arginine, which is basic and polar, at codon 3191 of the RYR1 protein (p.Gly3191Arg). This variant is present in population databases (rs756331568, gnomAD 0.004%). This missense change has been observed in individual(s) with clinical features of autosomal recessive RYR1-related conditions (PMID: 35693006; Invitae). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. ClinVar contains an entry for this variant (Variation ID: 436627). 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%. For these reasons, this variant has been classified as Pathogenic. - |
RYR1-related myopathy Pathogenic:1
Likely pathogenic, criteria provided, single submitter | provider interpretation | Pediatric Department, Peking University First Hospital | Feb 08, 2022 | - - |
Central core myopathy Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Center for Genomic Medicine, King Faisal Specialist Hospital and Research Center | Apr 04, 2024 | - - |
Malignant hyperthermia, susceptibility to, 1 Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | All of Us Research Program, National Institutes of Health | Apr 27, 2023 | - - |
not specified Benign:1
Likely benign, criteria provided, single submitter | clinical testing | Genetic Services Laboratory, University of Chicago | Jul 15, 2016 | - - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at