rs4802584

Variant names:

• chr19-38534726-C-G
• rs4802584
• NM_000540.3:c.11266C>G

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 Glutamine with Glutamic Acid at codon 3756 of the RYR1 protein, p.(Gln3756Glu). The maximum allele frequency for this variant among the six major gnomAD populations is AMR: 0.1085, 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/CA023907/MONDO:0007783/012

• Frequency:
  • Genomes: 𝑓 0.023 (93 hom., cov: 31)
  • Exomes 𝑓: 0.023 (729 hom.)
• Consequence: RYR1 NM_000540.3 missense
• Clinical Significance: Benign reviewed by expert panel B:18 O:1
• Conservation: PhyloP100: 8.16
• Publications: 22 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), ClinGen, Genomics England PanelApp, Ambry Genetics
• congenital multicore myopathy with external ophthalmoplegia

  Inheritance: AR Classification: DEFINITIVE, STRONG Submitted by: G2P, Genomics England PanelApp
• RYR1-related myopathy

  Inheritance: AR, AD Classification: DEFINITIVE Submitted by: ClinGen
• central core myopathy

  Inheritance: AD, AR Classification: STRONG, SUPPORTIVE Submitted by: Labcorp Genetics (formerly Invitae), Orphanet, 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

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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	RYR1	NM_000540.3	MANE Select	c.11266C>G	p.Gln3756Glu	missense	Exon 79 of 106	NP_000531.2
	RYR1	NM_001042723.2		c.11251C>G	p.Gln3751Glu	missense	Exon 78 of 105	NP_001036188.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	RYR1	ENST00000359596.8	TSL:5 MANE Select	c.11266C>G	p.Gln3756Glu	missense	Exon 79 of 106	ENSP00000352608.2
	RYR1	ENST00000355481.8	TSL:1	c.11251C>G	p.Gln3751Glu	missense	Exon 78 of 105	ENSP00000347667.3
	RYR1	ENST00000594335.6	TSL:1	n.*1994C>G		non_coding_transcript_exon	Exon 77 of 103	ENSP00000470927.2

Frequencies

GnomAD3 genomes AF: 0.0227 AC: 3452 AN: 152162 Hom.: 92 Cov.: 31

Gnomad AFR AF: 0.00777

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0725

Gnomad ASJ AF: 0.00173

Gnomad EAS AF: 0.0596

Gnomad SAS AF: 0.0327

Gnomad FIN AF: 0.0445

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.0151

Gnomad OTH AF: 0.0239

GnomAD2 exomes AF: 0.0345 AC: 8651 AN: 250408 AF XY: 0.0318

Gnomad AFR exome AF: 0.00730

Gnomad AMR exome AF: 0.109

Gnomad ASJ exome AF: 0.00209

Gnomad EAS exome AF: 0.0475

Gnomad FIN exome AF: 0.0448

Gnomad NFE exome AF: 0.0163

Gnomad OTH exome AF: 0.0280

GnomAD4 exome AF: 0.0228 AC: 33386 AN: 1461400 Hom.: 729 Cov.: 32 AF XY: 0.0226 AC XY: 16409 AN XY: 726938

African (AFR) AF: 0.00633 AC: 212 AN: 33476

American (AMR) AF: 0.108 AC: 4838 AN: 44618

Ashkenazi Jewish (ASJ) AF: 0.00226 AC: 59 AN: 26116

East Asian (EAS) AF: 0.0686 AC: 2720 AN: 39678

South Asian (SAS) AF: 0.0286 AC: 2466 AN: 86146

European-Finnish (FIN) AF: 0.0442 AC: 2360 AN: 53398

Middle Eastern (MID) AF: 0.00832 AC: 48 AN: 5768

European-Non Finnish (NFE) AF: 0.0172 AC: 19128 AN: 1111822

Other (OTH) AF: 0.0258 AC: 1555 AN: 60378

GnomAD4 genome AF: 0.0227 AC: 3455 AN: 152280 Hom.: 93 Cov.: 31 AF XY: 0.0254 AC XY: 1891 AN XY: 74452

African (AFR) AF: 0.00772 AC: 321 AN: 41562

American (AMR) AF: 0.0728 AC: 1113 AN: 15298

Ashkenazi Jewish (ASJ) AF: 0.00173 AC: 6 AN: 3470

East Asian (EAS) AF: 0.0596 AC: 308 AN: 5170

South Asian (SAS) AF: 0.0327 AC: 158 AN: 4826

European-Finnish (FIN) AF: 0.0445 AC: 472 AN: 10616

Middle Eastern (MID) AF: 0.00340 AC: 1 AN: 294

European-Non Finnish (NFE) AF: 0.0151 AC: 1026 AN: 68020

Other (OTH) AF: 0.0237 AC: 50 AN: 2112

Alfa AF: 0.0178 Hom.: 34

Bravo AF: 0.0239

TwinsUK AF: 0.0189 AC: 70

ALSPAC AF: 0.0202 AC: 78

ESP6500AA AF: 0.00590 AC: 26

ESP6500EA AF: 0.0149 AC: 128

ExAC AF: 0.0314 AC: 3818

Asia WGS AF: 0.0570 AC: 198 AN: 3478

EpiCase AF: 0.0130

EpiControl AF: 0.0138

ClinVar

ClinVar submissions as Germline

Significance: Benign

Revision: reviewed by expert panel

Pathogenic	VUS	Benign	Condition
-	-	6	not specified (6)
-	-	5	Malignant hyperthermia, susceptibility to, 1 (5)
-	-	3	not provided (4)
-	-	1	Central core myopathy (1)
-	-	1	Congenital multicore myopathy with external ophthalmoplegia (1)
-	-	1	Neuromuscular disease, congenital, with uniform type 1 fiber (1)
-	-	1	RYR1-related disorder (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.0052
BayesDel_addAF	Benign	-0.54	T
BayesDel_noAF	Benign	-0.47
CADD	Benign	21
DANN	Benign	0.96
DEOGEN2	Benign	0.29	T
Eigen	Benign	-0.82
Eigen_PC	Benign	-0.48
FATHMM_MKL	Benign	0.062	N
LIST_S2	Benign	0.69	T
MetaRNN	Benign	0.0014	T
MetaSVM	Benign	-0.98	T
MutationAssessor	Benign	-2.5	N
PhyloP100		8.2
PrimateAI	Uncertain	0.64	T
PROVEAN	Benign	2.4	N
REVEL	Uncertain	0.33
Sift	Benign	1.0	T
Sift4G	Benign	1.0	T
Polyphen		0.0	B
Vest4		0.058
MPC		0.62
ClinPred		0.015	T
GERP RS		4.8
Varity_R		0.054
gMVP		0.074
Mutation Taster		=96/4	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.080		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: rs4802584; hg19: chr19-39025366; COSMIC: COSV62093128; COSMIC: COSV62093128;