rs143987857

Variant names:

• chr19-38525492-G-A
• rs143987857
• NM_000540.3:c.10616G>A

Variant summary

Our verdict is Likely benign. The variant received -6 ACMG points: 2P and 8B. BS1 BS2 PP3_Moderate

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 arginine with histidine at codon 3539 of the RYR1 protein, p.(Arg3539His). The maximum allele frequency for this variant among the six major gnomAD populations is NFE: 0.00305, this is considered to be more common than expected for a pathogenic variant causing autosomal dominantly inherited MHS, BS1. This variant has been reported in 10 unrelated individuals who have a personal or family history of a malignant hyperthermia reaction, all of these individuals had a positive in vitro contracture test (IVCT) or caffeine halothane contracture test (CHCT) result (if the proband was unavailable for testing, a positive diagnostic test result in a mutation-positive relative was counted) (PMID:30236257; PMID:23460944; PMID:23558838; PMID:24433488; PMID:25960145), however, the high MAF in the NFE population precludes the use of PS4. This variant has been identified in multiple individuals with negative IVCT/CHCT results, BS2 (PMID:18253926, PMID:22473935). No functional studies were identified for this variant. This variant does not reside in a hotspot for pathogenic variants that contribute to MHS. A REVEL score >0.85 (0.877) supports a pathogenic status for this variant, PP3_Moderate. Based on using Bayes to combine criteria this variant is assessed as Likely Benign, (PMID:29300386). Criteria implemented: PP3_Moderate, BS1, BS2. LINK:https://erepo.genome.network/evrepo/ui/classification/CA023847/MONDO:0018493/012

• Frequency:
  • Genomes: 𝑓 0.0016 (0 hom., cov: 30)
  • Exomes 𝑓: 0.0022 (7 hom.)
• Consequence: RYR1 NM_000540.3 missense
• Clinical Significance: Likely benign reviewed by expert panel U:15 B:12 O:2
• Conservation: PhyloP100: 9.76
• 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), 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: Likely_benign. The variant received -6 ACMG points.

• PP3: For more information check the summary or visit ClinGen Evidence Repository.
• BS1: For more information check the summary or visit ClinGen Evidence Repository.
• BS2: 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.10616G>A	p.Arg3539His	missense	Exon 71 of 106	NP_000531.2	P21817-1
	RYR1	NM_001042723.2		c.10601G>A	p.Arg3534His	missense	Exon 70 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.10616G>A	p.Arg3539His	missense	Exon 71 of 106	ENSP00000352608.2	P21817-1
	RYR1	ENST00000355481.8	TSL:1	c.10601G>A	p.Arg3534His	missense	Exon 70 of 105	ENSP00000347667.3	P21817-2
	RYR1	ENST00000594335.6	TSL:1	n.*1344G>A		non_coding_transcript_exon	Exon 69 of 103	ENSP00000470927.2	M0R014

Frequencies

GnomAD3 genomes AF: 0.00165 AC: 251 AN: 151956 Hom.: 0 Cov.: 30

Gnomad AFR AF: 0.000556

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000262

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000416

Gnomad FIN AF: 0.00104

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00306

Gnomad OTH AF: 0.00144

GnomAD2 exomes AF: 0.00155 AC: 389 AN: 250486 AF XY: 0.00174

Gnomad AFR exome AF: 0.000495

Gnomad AMR exome AF: 0.0000869

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00102

Gnomad NFE exome AF: 0.00293

Gnomad OTH exome AF: 0.000817

GnomAD4 exome AF: 0.00224 AC: 3271 AN: 1461700 Hom.: 7 Cov.: 32 AF XY: 0.00215 AC XY: 1567 AN XY: 727156

African (AFR) AF: 0.000388 AC: 13 AN: 33476

American (AMR) AF: 0.000179 AC: 8 AN: 44692

Ashkenazi Jewish (ASJ) AF: 0.0000383 AC: 1 AN: 26128

East Asian (EAS) AF: 0.00 AC: 0 AN: 39698

South Asian (SAS) AF: 0.000522 AC: 45 AN: 86246

European-Finnish (FIN) AF: 0.000880 AC: 47 AN: 53384

Middle Eastern (MID) AF: 0.000348 AC: 2 AN: 5752

European-Non Finnish (NFE) AF: 0.00273 AC: 3038 AN: 1111936

Other (OTH) AF: 0.00194 AC: 117 AN: 60388

GnomAD4 genome AF: 0.00164 AC: 250 AN: 152074 Hom.: 0 Cov.: 30 AF XY: 0.00164 AC XY: 122 AN XY: 74344

African (AFR) AF: 0.000555 AC: 23 AN: 41468

American (AMR) AF: 0.000262 AC: 4 AN: 15260

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3468

East Asian (EAS) AF: 0.00 AC: 0 AN: 5180

South Asian (SAS) AF: 0.000208 AC: 1 AN: 4804

European-Finnish (FIN) AF: 0.00104 AC: 11 AN: 10608

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

European-Non Finnish (NFE) AF: 0.00306 AC: 208 AN: 67976

Other (OTH) AF: 0.00142 AC: 3 AN: 2108

Alfa AF: 0.00220 Hom.: 1

Bravo AF: 0.00144

TwinsUK AF: 0.00189 AC: 7

ALSPAC AF: 0.00467 AC: 18

ESP6500AA AF: 0.000681 AC: 3

ESP6500EA AF: 0.00244 AC: 21

ExAC AF: 0.00173 AC: 210

Asia WGS AF: 0.000577 AC: 2 AN: 3478

EpiCase AF: 0.00245

EpiControl AF: 0.00213

ClinVar

ClinVar submissions

Significance: Likely benign

Revision: reviewed by expert panel

Pathogenic	VUS	Benign	Condition
-	10	5	not provided (16)
-	1	3	Malignant hyperthermia, susceptibility to, 1 (4)
-	3	1	not specified (4)
-	-	1	Central core myopathy (1)
-	-	1	Malignant hyperthermia of anesthesia (1)
-	-	1	RYR1-related disorder (2)
-	1	-	RYR1-related myopathy (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.59
BayesDel_addAF	Uncertain	0.047	T
BayesDel_noAF	Pathogenic	0.30
CADD	Uncertain	25
DANN	Uncertain	0.99
DEOGEN2	Pathogenic	0.82	D
Eigen	Pathogenic	0.72
Eigen_PC	Uncertain	0.62
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Uncertain	0.97	D
M_CAP	Pathogenic	0.38	D
MetaRNN	Benign	0.090	T
MetaSVM	Pathogenic	1.1	D
MutationAssessor	Uncertain	2.3	M
PhyloP100		9.8
PrimateAI	Uncertain	0.62	T
PROVEAN	Pathogenic	-4.4	D
REVEL	Pathogenic	0.88
Sift	Uncertain	0.0020	D
Polyphen		1.0	D
Vest4		0.71
MVP		0.98
MPC		0.38
ClinPred		0.059	T
GERP RS		3.1
Varity_R		0.41
gMVP		0.50
Mutation Taster		=64/36	polymorphism

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: rs143987857; hg19: chr19-39016132; COSMIC: COSV62094702; COSMIC: COSV62094702;