NM_000540.3:c.10747G>C

Variant names:

• chr19-38527707-G-C
• rs55876273
• NM_000540.3:c.10747G>C

Variant summary

Our verdict is Benign. The variant received -8 ACMG points: 0P and 8B. BA1

This summary comes from the ClinGen Evidence Repository: This pathogenicity assessment is relevant only for malignant hyperthermia susceptibility (MHS) inherited in an autosomal dominant pattern. Variants in RYR1 can also cause other myopathies inherited in an autosomal dominant pattern or in an autosomal recessive pattern. Some of these disorders may predispose individuals to malignant hyperthermia. RYR1 variants may also contribute to a malignant hyperthermia reaction in combination with other genetic and non-genetic factors and the clinician needs to consider such factors in making management decisions.This sequence variant predicts a substitution of Glutamic Acid with Glutamine at codon 3583 of the RYR1 protein, p.(Glu3583Gln). The maximum allele frequency for this variant among the six major gnomAD populations is SAS: 0.0241, which is considered to be too common for a pathogenic variant causing autosomal dominantly inherited MHS, BA1. This variant has been classified as Benign. Criteria implemented: BA1. LINK:https://erepo.genome.network/evrepo/ui/classification/CA023858/MONDO:0007783/012

• Frequency:
  • Genomes: 𝑓 0.013 (22 hom., cov: 31)
  • Exomes 𝑓: 0.020 (368 hom.)
• Consequence: RYR1 NM_000540.3 missense
• Clinical Significance: Benign reviewed by expert panel B:20 O:1
• Conservation: PhyloP100: 3.38
• Publications: 23 publications found

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]

RYR1 Gene-Disease associations (from GenCC):

• malignant hyperthermia, susceptibility to, 1

  Inheritance: AD Classification: DEFINITIVE, STRONG Submitted by: Labcorp Genetics (formerly Invitae), PanelApp Australia, Genomics England PanelApp, Ambry Genetics, ClinGen
• RYR1-related myopathy

  Inheritance: AD, AR Classification: DEFINITIVE, STRONG Submitted by: ClinGen, PanelApp Australia
• congenital multicore myopathy with external ophthalmoplegia

  Inheritance: AR Classification: DEFINITIVE, STRONG Submitted by: G2P, Genomics England PanelApp
• central core myopathy

  Inheritance: AD, AR Classification: STRONG, SUPPORTIVE Submitted by: Orphanet, Labcorp Genetics (formerly Invitae), Genomics England PanelApp
• King-Denborough syndrome

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• malignant hyperthermia of anesthesia

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• autosomal recessive centronuclear myopathy

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet
• benign Samaritan congenital myopathy

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet
• congenital myopathy with myasthenic-like onset

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet
• lethal multiple pterygium syndrome

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

ENSG00000269445 (HGNC:):

ACMG classification

Our verdict: Benign. The variant received -8 ACMG points.

• BA1: For more information check the summary or visit ClinGen Evidence Repository.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_000540.3. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	RYR1	NM_000540.3	MANE Select	c.10747G>C	p.Glu3583Gln	missense	Exon 73 of 106	NP_000531.2	P21817-1
	RYR1	NM_001042723.2		c.10732G>C	p.Glu3578Gln	missense	Exon 72 of 105	NP_001036188.1	P21817-2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	RYR1	ENST00000359596.8	TSL:5 MANE Select	c.10747G>C	p.Glu3583Gln	missense	Exon 73 of 106	ENSP00000352608.2	P21817-1
	RYR1	ENST00000355481.8	TSL:1	c.10732G>C	p.Glu3578Gln	missense	Exon 72 of 105	ENSP00000347667.3	P21817-2
	RYR1	ENST00000594335.6	TSL:1	n.*1475G>C		non_coding_transcript_exon	Exon 71 of 103	ENSP00000470927.2	M0R014

Frequencies

GnomAD3 genomes AF: 0.0126 AC: 1911 AN: 152176 Hom.: 22 Cov.: 31

Gnomad AFR AF: 0.00376

Gnomad AMI AF: 0.00219

Gnomad AMR AF: 0.00759

Gnomad ASJ AF: 0.000288

Gnomad EAS AF: 0.000386

Gnomad SAS AF: 0.0249

Gnomad FIN AF: 0.0187

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0189

Gnomad OTH AF: 0.0148

GnomAD2 exomes AF: 0.0150 AC: 3764 AN: 251162 AF XY: 0.0161

Gnomad AFR exome AF: 0.00333

Gnomad AMR exome AF: 0.00682

Gnomad ASJ exome AF: 0.000199

Gnomad EAS exome AF: 0.000163

Gnomad FIN exome AF: 0.0214

Gnomad NFE exome AF: 0.0192

Gnomad OTH exome AF: 0.0142

GnomAD4 exome AF: 0.0200 AC: 29244 AN: 1461824 Hom.: 368 Cov.: 33 AF XY: 0.0201 AC XY: 14604 AN XY: 727216

African (AFR) AF: 0.00275 AC: 92 AN: 33480

American (AMR) AF: 0.00675 AC: 302 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.000153 AC: 4 AN: 26136

East Asian (EAS) AF: 0.0000756 AC: 3 AN: 39698

South Asian (SAS) AF: 0.0259 AC: 2237 AN: 86254

European-Finnish (FIN) AF: 0.0200 AC: 1069 AN: 53370

Middle Eastern (MID) AF: 0.00954 AC: 55 AN: 5768

European-Non Finnish (NFE) AF: 0.0220 AC: 24449 AN: 1112004

Other (OTH) AF: 0.0171 AC: 1033 AN: 60390

GnomAD4 genome AF: 0.0125 AC: 1911 AN: 152292 Hom.: 22 Cov.: 31 AF XY: 0.0127 AC XY: 944 AN XY: 74468

African (AFR) AF: 0.00375 AC: 156 AN: 41560

American (AMR) AF: 0.00758 AC: 116 AN: 15302

Ashkenazi Jewish (ASJ) AF: 0.000288 AC: 1 AN: 3472

East Asian (EAS) AF: 0.000387 AC: 2 AN: 5172

South Asian (SAS) AF: 0.0251 AC: 121 AN: 4820

European-Finnish (FIN) AF: 0.0187 AC: 199 AN: 10626

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.0189 AC: 1283 AN: 68022

Other (OTH) AF: 0.0147 AC: 31 AN: 2112

Alfa AF: 0.0151 Hom.: 18

Bravo AF: 0.0110

TwinsUK AF: 0.0183 AC: 68

ALSPAC AF: 0.0184 AC: 71

ESP6500AA AF: 0.00386 AC: 17

ESP6500EA AF: 0.0181 AC: 156

ExAC AF: 0.0149 AC: 1807

Asia WGS AF: 0.00808 AC: 28 AN: 3478

EpiCase AF: 0.0165

EpiControl AF: 0.0190

ClinVar

ClinVar submissions

Significance: Benign

Revision: reviewed by expert panel

Pathogenic	VUS	Benign	Condition
-	-	7	not specified (7)
-	-	4	Malignant hyperthermia, susceptibility to, 1 (4)
-	-	4	not provided (5)
-	-	1	Central core myopathy (1)
-	-	1	Congenital multicore myopathy with external ophthalmoplegia (1)
-	-	1	Congenital myopathy with fiber type disproportion;C1840365:King Denborough syndrome;C1850674:Congenital multicore myopathy with external ophthalmoplegia;C2930980:Malignant hyperthermia, susceptibility to, 1;C5830701:Central core myopathy (1)
-	-	1	Malignant hypothermia (1)
-	-	1	RYR1-related disorder (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.11
BayesDel_addAF	Benign	-0.34	T
BayesDel_noAF	Benign	-0.24
CADD	Benign	21
DANN	Benign	0.93
DEOGEN2	Benign	0.33	T
Eigen	Benign	-0.039
Eigen_PC	Benign	0.038
FATHMM_MKL	Uncertain	0.91	D
LIST_S2	Benign	0.74	T
MetaRNN	Benign	0.0076	T
MetaSVM	Uncertain	0.093	D
MutationAssessor	Benign	0.32	N
PhyloP100		3.4
PrimateAI	Benign	0.44	T
PROVEAN	Benign	-0.75	N
REVEL	Uncertain	0.32
Sift	Benign	0.23	T
Polyphen		0.66	P
Vest4		0.38
MPC		0.57
ClinPred		0.024	T
GERP RS		4.7
Varity_R		0.12
gMVP		0.16
Mutation Taster		=97/3	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.0		Details are displayed if max score is > 0.2

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

Other links and lift over

dbSNP: rs55876273; hg19: chr19-39018347;