rs35180584

Variant names:

Your query was ambiguous. Multiple possible variants found:

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 threonine with serine at codon 2787 of the RYR1 protein, p.(Thr2787Ser). The maximum allele frequency for this variant among the six major gnomAD populations is AFR: 0.029867, 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/CA024914/MONDO:0018493/012

Frequency

Genomes: 𝑓 0.0088 ( 20 hom., cov: 32)

Exomes 𝑓: 0.0013 ( 19 hom. )

Consequence

RYR1
NM_000540.3 missense

Scores

Clinical Significance

Benign reviewed by expert panel B:20O:1

Conservation

PhyloP100: 5.60

Publications

15 publications found

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]

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

RYR1 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

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.8360C>G	p.Thr2787Ser	missense	Exon 53 of 106	NP_000531.2
	RYR1	NM_001042723.2		c.8360C>G	p.Thr2787Ser	missense	Exon 53 of 105	NP_001036188.1

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein
RYR1	ENST00000359596.8	TSL:5 MANE Select	c.8360C>G	p.Thr2787Ser	missense	Exon 53 of 106	ENSP00000352608.2
RYR1	ENST00000355481.8	TSL:1	c.8360C>G	p.Thr2787Ser	missense	Exon 53 of 105	ENSP00000347667.3
RYR1	ENST00000594335.6	TSL:1	n.8360C>G		non_coding_transcript_exon	Exon 53 of 103	ENSP00000470927.2

Frequencies

GnomAD3 genomes

AF:

0.00873

AC:

1329

AN:

152166

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0290

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00281

Gnomad ASJ

AF:

0.0115

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.000414

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000441

Gnomad OTH

AF:

0.00718

GnomAD2 exomes

AF:

0.00291

AC:

724

AN:

249108

AF XY:

0.00228

show subpopulations

Gnomad AFR exome

AF:

0.0308

Gnomad AMR exome

AF:

0.00282

Gnomad ASJ exome

AF:

0.0100

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.000346

Gnomad OTH exome

AF:

0.000491

GnomAD4 exome

AF:

0.00130

AC:

1892

AN:

1460090

Hom.:

Cov.:

AF XY:

0.00117

AC XY:

851

AN XY:

726194

show subpopulations

African (AFR)

AF:

0.0304

AC:

1014

AN:

33408

American (AMR)

AF:

0.00285

AC:

127

AN:

44544

Ashkenazi Jewish (ASJ)

AF:

0.00998

AC:

260

AN:

26054

East Asian (EAS)

AF:

0.00

AC:

AN:

39698

South Asian (SAS)

AF:

0.000186

AC:

AN:

85860

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53352

Middle Eastern (MID)

AF:

0.00287

AC:

AN:

5572

European-Non Finnish (NFE)

AF:

0.000253

AC:

281

AN:

1111262

Other (OTH)

AF:

0.00295

AC:

178

AN:

60340

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.459

Heterozygous variant carriers

188

281

375

469

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

120

160

200

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.00875

AC:

1333

AN:

152284

Hom.:

Cov.:

AF XY:

0.00830

AC XY:

618

AN XY:

74464

show subpopulations

African (AFR)

AF:

0.0290

AC:

1204

AN:

41532

American (AMR)

AF:

0.00281

AC:

AN:

15302

Ashkenazi Jewish (ASJ)

AF:

0.0115

AC:

AN:

3472

East Asian (EAS)

AF:

0.00

AC:

AN:

5186

South Asian (SAS)

AF:

0.000207

AC:

AN:

4822

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10616

Middle Eastern (MID)

AF:

0.00

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.000441

AC:

AN:

68036

Other (OTH)

AF:

0.00710

AC:

AN:

2112

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.503

Heterozygous variant carriers

142

212

283

354

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

100

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.00138

Hom.:

Bravo

AF:

0.0103

TwinsUK

AF:

0.000539

AC:

ALSPAC

AF:

0.00104

AC:

ESP6500AA

AF:

0.0293

AC:

129

ESP6500EA

AF:

0.000465

AC:

ExAC

AF:

0.00307

AC:

373

Asia WGS

AF:

0.00289

AC:

AN:

3478

EpiCase

AF:

0.000545

EpiControl

AF:

0.000831

ClinVar

ClinVar submissions as Germline

Significance:Benign

Revision:reviewed by expert panel

View on ClinVar

Pathogenic

VUS

Benign

Condition

not provided (6)

not specified (4)

Malignant hyperthermia, susceptibility to, 1 (3)

RYR1-related disorder (2)

Central core myopathy (1)

Congenital multicore myopathy with external ophthalmoplegia (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)

Malignant hyperthermia of anesthesia (1)

Malignant hypothermia (1)

Neuromuscular disease, congenital, with uniform type 1 fiber (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.18

BayesDel_addAF

Benign

-0.29

BayesDel_noAF

Benign

-0.17

CADD

Benign

(source)

DANN

Benign

0.90

DEOGEN2

Uncertain

0.66

Eigen

Benign

0.077

Eigen_PC

Benign

0.18

FATHMM_MKL

Pathogenic

0.98

LIST_S2

Benign

0.82

MetaRNN

Benign

0.013

MetaSVM

Uncertain

-0.072

MutationAssessor

Benign

1.7

PhyloP100

5.6

PrimateAI

Uncertain

0.77

PROVEAN

Uncertain

-2.7

REVEL

Uncertain

0.47

Sift

Benign

0.12

Polyphen

0.0070

Vest4

0.62

MutPred

0.78

Gain of disorder (P = 0.0499)

MVP

0.97

MPC

0.27

ClinPred

0.023

GERP RS

4.1

Varity_R

0.34

gMVP

0.31

Mutation Taster

=90/10

polymorphism

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

Splicevardb

2.0

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

Publications

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over