chr19-38466176-C-T
Variant summary
Our verdict is Uncertain significance. Variant got 2 ACMG points: 2P and 0B. PP2PP3
The NM_000540.3(RYR1):c.2956C>T(p.Arg986Cys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000143 in 1,613,514 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). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R986H) 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 2 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
RYR1 | NM_000540.3 | c.2956C>T | p.Arg986Cys | missense_variant | 24/106 | ENST00000359596.8 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
RYR1 | ENST00000359596.8 | c.2956C>T | p.Arg986Cys | missense_variant | 24/106 | 5 | NM_000540.3 | A2 | |
RYR1 | ENST00000355481.8 | c.2956C>T | p.Arg986Cys | missense_variant | 24/105 | 1 | P4 | ||
RYR1 | ENST00000594111.1 | n.49C>T | non_coding_transcript_exon_variant | 1/2 | 2 | ||||
RYR1 | ENST00000599547.6 | c.2956C>T | p.Arg986Cys | missense_variant, NMD_transcript_variant | 24/80 | 2 |
Frequencies
GnomAD3 genomes AF: 0.0000789 AC: 12AN: 152184Hom.: 0 Cov.: 32
GnomAD3 exomes AF: 0.0000603 AC: 15AN: 248634Hom.: 0 AF XY: 0.0000519 AC XY: 7AN XY: 134824
GnomAD4 exome AF: 0.000149 AC: 218AN: 1461212Hom.: 0 Cov.: 41 AF XY: 0.000136 AC XY: 99AN XY: 726980
GnomAD4 genome AF: 0.0000788 AC: 12AN: 152302Hom.: 0 Cov.: 32 AF XY: 0.0000537 AC XY: 4AN XY: 74486
ClinVar
Submissions by phenotype
Malignant hyperthermia, susceptibility to, 1 Uncertain:3
Uncertain significance, criteria provided, single submitter | clinical testing | Color Diagnostics, LLC DBA Color Health | Feb 15, 2023 | This missense variant replaces arginine with cysteine at codon 986 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 autosomal dominant malignant hyperthermia susceptibility in the literature, although it is associated with other phenotypes (ClinVar Variation ID: 161367). This variant has been identified in 17/280012 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. - |
Uncertain significance, criteria provided, single submitter | research | Biesecker Lab/Clinical Genomics Section, National Institutes of Health | Jul 01, 2013 | - - |
Uncertain significance, criteria provided, single submitter | clinical testing | All of Us Research Program, National Institutes of Health | Feb 05, 2024 | This missense variant replaces arginine with cysteine at codon 986 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 autosomal dominant malignant hyperthermia susceptibility in the literature, although it is associated with other phenotypes (ClinVar Variation ID: 161367). This variant has been identified in 17/280012 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. - |
not provided Uncertain:2
Uncertain significance, criteria provided, single submitter | clinical testing | Revvity Omics, Revvity | Sep 10, 2019 | - - |
Uncertain significance, criteria provided, single submitter | clinical testing | GeneDx | Oct 18, 2019 | Not observed at a significant frequency in large population cohorts (Lek et al., 2016); In silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect; Reported in the compound heterozygous state in an individual with congenital myopathy (Klein et al., 2012); This variant is associated with the following publications: (PMID: 26332594, 22473935, 24195946, 25637381, 24055113) - |
RYR1-related disorder Pathogenic:1
Likely pathogenic, criteria provided, single submitter | clinical testing | Invitae | Jan 27, 2024 | This sequence change replaces arginine, which is basic and polar, with cysteine, which is neutral and slightly polar, at codon 986 of the RYR1 protein (p.Arg986Cys). This variant is present in population databases (rs150993059, gnomAD 0.01%). This missense change has been observed in individual(s) with autosomal recessive congenital myopathy (PMID: 22473935). 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: 161367). 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 currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic. - |
not specified Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Women's Health and Genetics/Laboratory Corporation of America, LabCorp | May 16, 2022 | Variant summary: RYR1 c.2956C>T (p.Arg986Cys) results in a non-conservative amino acid change located in the Ryanodine receptor Ryr domain (IPR003032) of the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 6e-05 in 248634 control chromosomes (gnomAD). This frequency is not significantly higher than expected for a pathogenic variant in RYR1 causing Malignant Hyperthermia Susceptibility (6e-05 vs 8.8e-05), allowing no conclusion about variant significance. c.2956C>T has been reported in the literature in individuals affected with Myopathy (Klein_2012). These data do not allow any conclusion about variant significance. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Two ClinVar submitters have assessed the variant since 2014: both classified the variant as of uncertain significance. Based on the evidence outlined above, the variant was classified as uncertain significance. - |
Congenital myopathy Uncertain:1
Uncertain significance, no assertion criteria provided | research | CSER _CC_NCGL, University of Washington | Jun 01, 2014 | - - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at