Menu
GeneBe

rs118192172

Variant summary

Our verdict is Pathogenic. Variant got 13 ACMG points: 13P and 0B. PM1PM2PM5PP2PP3_StrongPP5_Moderate

The NM_000540.3(RYR1):c.1840C>G(p.Arg614Gly) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD Genomes project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R614C) has been classified as Pathogenic.

Frequency

Genomes: not found (cov: 30)

Consequence

RYR1
NM_000540.3 missense

Scores

9
7
1

Clinical Significance

Likely pathogenic criteria provided, single submitter P:1

Conservation

PhyloP100: 2.77
Variant links:
Genes affected
RYR1 (HGNC:10483): (ryanodine receptor 1) This gene encodes a ryanodine receptor found in skeletal muscle. The encoded protein functions as a calcium release channel in the sarcoplasmic reticulum but also serves to connect the sarcoplasmic reticulum and transverse tubule. Mutations in this gene are associated with malignant hyperthermia susceptibility, central core disease, and minicore myopathy with external ophthalmoplegia. Alternatively spliced transcripts encoding different isoforms have been described. [provided by RefSeq, Jul 2008]

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Pathogenic. Variant got 13 ACMG points.

PM1
In a hotspot region, there are 2 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 7 uncertain in NM_000540.3
PM2
Very rare variant in population databases, with high coverage;
PM5
Other missense variant is known to change same aminoacid residue: Variant chr19-38457545-C-T is described in ClinVar as [Pathogenic, drug_response]. Clinvar id is 12964.Status of the report is reviewed_by_expert_panel, 3 stars.
PP2
Missense variant where missense usually causes diseases, RYR1
PP3
MetaRNN computational evidence supports a deleterious effect, 0.972
PP5
Variant 19-38457545-C-G is Pathogenic according to our data. Variant chr19-38457545-C-G is described in ClinVar as [Likely_pathogenic]. Clinvar id is 544395.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE UniProt
RYR1NM_000540.3 linkuse as main transcriptc.1840C>G p.Arg614Gly missense_variant 17/106 ENST00000359596.8

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Appris UniProt
RYR1ENST00000359596.8 linkuse as main transcriptc.1840C>G p.Arg614Gly missense_variant 17/1065 NM_000540.3 A2P21817-1
RYR1ENST00000355481.8 linkuse as main transcriptc.1840C>G p.Arg614Gly missense_variant 17/1051 P4P21817-2
RYR1ENST00000599547.6 linkuse as main transcriptc.1840C>G p.Arg614Gly missense_variant, NMD_transcript_variant 17/802

Frequencies

GnomAD3 genomes
Cov.:
30
GnomAD4 exome
Cov.:
33
GnomAD4 genome
Cov.:
30

ClinVar

Significance: Likely pathogenic
Submissions summary: Pathogenic:1
Revision: criteria provided, single submitter
LINK: link

Submissions by phenotype

RYR1-Related Disorders Pathogenic:1
Likely pathogenic, criteria provided, single submitterclinical testingInvitaeMar 23, 2023This variant is not present in population databases (gnomAD no frequency). 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. This variant disrupts the p.Arg614 amino acid residue in RYR1. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 1774074, 8602662, 10352931, 11493496, 11668625, 12411788). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. 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. ClinVar contains an entry for this variant (Variation ID: 544395). This missense change has been observed in individual(s) with autosomal dominant malignant hyperthermia susceptibility (Invitae). This sequence change replaces arginine, which is basic and polar, with glycine, which is neutral and non-polar, at codon 614 of the RYR1 protein (p.Arg614Gly). -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Pathogenic
0.99
BayesDel_addAF
Pathogenic
0.34
D
BayesDel_noAF
Pathogenic
0.25
Cadd
Uncertain
25
Dann
Uncertain
1.0
Eigen
Uncertain
0.63
Eigen_PC
Uncertain
0.52
FATHMM_MKL
Uncertain
0.91
D
LIST_S2
Pathogenic
0.99
D;D
M_CAP
Pathogenic
0.56
D
MetaRNN
Pathogenic
0.97
D;D
MetaSVM
Pathogenic
1.0
D
MutationAssessor
Uncertain
2.8
M;M
MutationTaster
Benign
1.0
D;D;D
PrimateAI
Uncertain
0.75
T
PROVEAN
Pathogenic
-6.5
D;D
REVEL
Pathogenic
0.92
Sift
Uncertain
0.0030
D;D
Polyphen
1.0
D;D
Vest4
0.76
MutPred
0.86
Loss of sheet (P = 0.0817);Loss of sheet (P = 0.0817);
MVP
0.97
MPC
1.2
ClinPred
0.99
D
GERP RS
3.8
Varity_R
0.80
gMVP
0.71

Splicing

Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
0.060
Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Below is the list of publications found by LitVar. It may be empty.

Other links and lift over

dbSNP: rs118192172; hg19: chr19-38948185; API