NM_000540.3:c.5360C>T

Variant names:

• chr19-38486015-C-T
• rs34934920
• NM_000540.3:c.5360C>T

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 Proline with Leucine at codon 1787 of the RYR1 protein, p.(Pro1787Leu). The maximum allele frequency for this variant among the six major gnomAD populations is SAS: 0.0413, 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/CA024515/MONDO:0007783/012

• Frequency:
  • Genomes: 𝑓 0.017 (48 hom., cov: 32)
  • Exomes 𝑓: 0.023 (502 hom.)
• Consequence: RYR1 NM_000540.3 missense
• Clinical Significance: Benign reviewed by expert panel B:21 O:1
• Conservation: PhyloP100: 0.765
• Publications: 34 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

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.5360C>T	p.Pro1787Leu	missense	Exon 34 of 106	NP_000531.2	P21817-1
	RYR1	NM_001042723.2		c.5360C>T	p.Pro1787Leu	missense	Exon 34 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.5360C>T	p.Pro1787Leu	missense	Exon 34 of 106	ENSP00000352608.2	P21817-1
	RYR1	ENST00000355481.8	TSL:1	c.5360C>T	p.Pro1787Leu	missense	Exon 34 of 105	ENSP00000347667.3	P21817-2
	RYR1	ENST00000594335.6	TSL:1	n.5360C>T		non_coding_transcript_exon	Exon 34 of 103	ENSP00000470927.2	M0R014

Frequencies

GnomAD3 genomes AF: 0.0169 AC: 2572 AN: 152230 Hom.: 49 Cov.: 32

Gnomad AFR AF: 0.00461

Gnomad AMI AF: 0.0263

Gnomad AMR AF: 0.0175

Gnomad ASJ AF: 0.0277

Gnomad EAS AF: 0.000192

Gnomad SAS AF: 0.0484

Gnomad FIN AF: 0.00612

Gnomad MID AF: 0.0475

Gnomad NFE AF: 0.0240

Gnomad OTH AF: 0.0215

GnomAD2 exomes AF: 0.0195 AC: 4749 AN: 243108 AF XY: 0.0214

Gnomad AFR exome AF: 0.00337

Gnomad AMR exome AF: 0.0120

Gnomad ASJ exome AF: 0.0252

Gnomad EAS exome AF: 0.000165

Gnomad FIN exome AF: 0.00671

Gnomad NFE exome AF: 0.0232

Gnomad OTH exome AF: 0.0237

GnomAD4 exome AF: 0.0235 AC: 34311 AN: 1461176 Hom.: 502 Cov.: 33 AF XY: 0.0242 AC XY: 17599 AN XY: 726918

African (AFR) AF: 0.00415 AC: 139 AN: 33474

American (AMR) AF: 0.0134 AC: 599 AN: 44712

Ashkenazi Jewish (ASJ) AF: 0.0263 AC: 687 AN: 26114

East Asian (EAS) AF: 0.000302 AC: 12 AN: 39692

South Asian (SAS) AF: 0.0421 AC: 3634 AN: 86252

European-Finnish (FIN) AF: 0.00646 AC: 342 AN: 52910

Middle Eastern (MID) AF: 0.0368 AC: 212 AN: 5768

European-Non Finnish (NFE) AF: 0.0246 AC: 27338 AN: 1111876

Other (OTH) AF: 0.0223 AC: 1348 AN: 60378

GnomAD4 genome AF: 0.0169 AC: 2569 AN: 152348 Hom.: 48 Cov.: 32 AF XY: 0.0166 AC XY: 1235 AN XY: 74498

African (AFR) AF: 0.00459 AC: 191 AN: 41580

American (AMR) AF: 0.0175 AC: 268 AN: 15310

Ashkenazi Jewish (ASJ) AF: 0.0277 AC: 96 AN: 3470

East Asian (EAS) AF: 0.000193 AC: 1 AN: 5188

South Asian (SAS) AF: 0.0479 AC: 231 AN: 4826

European-Finnish (FIN) AF: 0.00612 AC: 65 AN: 10628

Middle Eastern (MID) AF: 0.0510 AC: 15 AN: 294

European-Non Finnish (NFE) AF: 0.0240 AC: 1633 AN: 68028

Other (OTH) AF: 0.0213 AC: 45 AN: 2112

Alfa AF: 0.0230 Hom.: 75

Bravo AF: 0.0164

TwinsUK AF: 0.0289 AC: 107

ALSPAC AF: 0.0306 AC: 118

ESP6500AA AF: 0.00409 AC: 18

ESP6500EA AF: 0.0232 AC: 199

ExAC AF: 0.0191 AC: 2315

Asia WGS AF: 0.0130 AC: 46 AN: 3478

EpiCase AF: 0.0281

EpiControl AF: 0.0259

ClinVar

ClinVar submissions

Significance: Benign

Revision: reviewed by expert panel

Pathogenic	VUS	Benign	Condition
-	-	6	not specified (6)
-	-	5	Malignant hyperthermia, susceptibility to, 1 (5)
-	-	5	not provided (6)
-	-	1	Central core myopathy (1)
-	-	1	Congenital multicore myopathy with external ophthalmoplegia (1)
-	-	1	Malignant hypothermia (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	0.15
BayesDel_addAF	Benign	-0.52	T
BayesDel_noAF	Benign	-0.49
CADD	Benign	18
DANN	Uncertain	0.99
DEOGEN2	Uncertain	0.59	D
Eigen	Benign	-0.92
Eigen_PC	Benign	-0.85
FATHMM_MKL	Benign	0.22	N
LIST_S2	Benign	0.84	T
MetaRNN	Benign	0.0031	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	-0.14	N
PhyloP100		0.77
PrimateAI	Uncertain	0.61	T
PROVEAN	Uncertain	-2.9	D
REVEL	Benign	0.055
Sift	Benign	0.10	T
Polyphen		0.016	B
Vest4		0.32
MPC		0.66
ClinPred		0.020	T
GERP RS		-0.016
Varity_R		0.059
gMVP		0.53
Mutation Taster		=100/0	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: rs34934920; hg19: chr19-38976655;