rs118192168

Variant names:

• chr19-38580403-G-A
• rs118192168
• NM_000540.3:c.14545G>A

Your query was ambiguous. Multiple possible variants found:

• chr19-38580403-G-A
• chr19-38580403-G-T

Variant summary

Our verdict is Pathogenic. The variant received 11 ACMG points: 11P and 0B. PM1_Supporting PS4 PS3_Moderate PP1_Strong

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 valine with isoleucine at codon 4849 of the RYR1 protein, p.(Val4849Ile). The maximum allele frequency for this variant among the six major gnomAD populations is AFR: 0.00004, a frequency consistent with pathogenicity for MHS. This variant has been reported in 31 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), PS4 (PMID:25960145, 30236257, 23558838, 24433488, 16163667, 28527222, 15731587, 19346234, 21455645). Functional studies in HEK293 cells show an increased sensitivity to RYR1 agonists PS3_Moderate (PMID:28403410). This variant resides in a region of RYR1 considered to be a hotspot for pathogenic variants that contribute to MHS, PM1_Sup (PMID:21118704). This variant segregates with MHS in 23 individuals, PP1_Strong (PMID:25960145, 28527222). A REVEL score of 0.817 supports neither a pathogenic nor a benign status for this variant. This variant has been classified as Pathogenic. Criteria implemented: PS3_Moderate, PS4, PM1_Supporting, PP1_Strong. LINK:https://erepo.genome.network/evrepo/ui/classification/CA024171/MONDO:0007783/012

• Frequency:
  • Genomes: 𝑓 0.0000066 (0 hom., cov: 31)
  • Exomes 𝑓: 0.000020 (0 hom.)
• Consequence: RYR1 NM_000540.3 missense
• Clinical Significance: drug response reviewed by expert panel P:19 O:8
• Conservation: PhyloP100: 8.10
• Publications: 33 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: Pathogenic. The variant received 11 ACMG points.

• PS3: For more information check the summary or visit ClinGen Evidence Repository.
• PS4: For more information check the summary or visit ClinGen Evidence Repository.
• PM1: For more information check the summary or visit ClinGen Evidence Repository.
• PP1: 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.14545G>A	p.Val4849Ile	missense	Exon 101 of 106	NP_000531.2	P21817-1
	RYR1	NM_001042723.2		c.14530G>A	p.Val4844Ile	missense	Exon 100 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.14545G>A	p.Val4849Ile	missense	Exon 101 of 106	ENSP00000352608.2	P21817-1
	RYR1	ENST00000355481.8	TSL:1	c.14530G>A	p.Val4844Ile	missense	Exon 100 of 105	ENSP00000347667.3	P21817-2
	RYR1	ENST00000594335.6	TSL:1	n.*5255G>A		non_coding_transcript_exon	Exon 98 of 103	ENSP00000470927.2	M0R014

Frequencies

GnomAD3 genomes AF: 0.00000657 AC: 1 AN: 152138 Hom.: 0 Cov.: 31

Gnomad AFR AF: 0.0000241

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.0000159 AC: 4 AN: 251422 AF XY: 0.0000221

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000289

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000264

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000198 AC: 29 AN: 1461856 Hom.: 0 Cov.: 34 AF XY: 0.0000206 AC XY: 15 AN XY: 727224

African (AFR) AF: 0.00 AC: 0 AN: 33480

American (AMR) AF: 0.0000224 AC: 1 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26136

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

South Asian (SAS) AF: 0.00 AC: 0 AN: 86258

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53398

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5768

European-Non Finnish (NFE) AF: 0.0000252 AC: 28 AN: 1112000

Other (OTH) AF: 0.00 AC: 0 AN: 60394

GnomAD4 genome AF: 0.00000657 AC: 1 AN: 152138 Hom.: 0 Cov.: 31 AF XY: 0.0000135 AC XY: 1 AN XY: 74318

African (AFR) AF: 0.0000241 AC: 1 AN: 41424

American (AMR) AF: 0.00 AC: 0 AN: 15262

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3472

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

South Asian (SAS) AF: 0.00 AC: 0 AN: 4828

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10624

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 316

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 68028

Other (OTH) AF: 0.00 AC: 0 AN: 2092

Alfa AF: 0.0000261 Hom.: 0

Bravo AF: 0.00000378

ExAC AF: 0.00000824 AC: 1

EpiCase AF: 0.00

EpiControl AF: 0.0000593

ClinVar

ClinVar submissions

Significance: drug response

Revision: reviewed by expert panel

Pathogenic	VUS	Benign	Condition
7	-	-	Malignant hyperthermia, susceptibility to, 1 (7)
4	-	-	not provided (5)
2	-	-	Congenital multicore myopathy with external ophthalmoplegia (2)
2	-	-	RYR1-related disorder (2)
1	-	-	Centronuclear myopathy (1)
1	-	-	Inborn genetic diseases (1)
1	-	-	Malignant hyperthermia of anesthesia (1)
1	-	-	RYR1-related myopathy (1)
-	-	-	desflurane response - Toxicity (1)
-	-	-	enflurane response - Toxicity (1)
-	-	-	halothane response - Toxicity (1)
-	-	-	isoflurane response - Toxicity (1)
-	-	-	methoxyflurane response - Toxicity (1)
-	-	-	sevoflurane response - Toxicity (1)
-	-	-	succinylcholine response - Toxicity (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.58
BayesDel_addAF	Pathogenic	0.37	D
BayesDel_noAF	Pathogenic	0.37
CADD	Uncertain	25
DANN	Uncertain	0.98
DEOGEN2	Uncertain	0.68	D
Eigen	Uncertain	0.57
Eigen_PC	Uncertain	0.58
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.96	D
M_CAP	Uncertain	0.18	D
MetaRNN	Pathogenic	0.79	D
MetaSVM	Pathogenic	1.0	D
MutationAssessor	Benign	0.83	L
PhyloP100		8.1
PrimateAI	Uncertain	0.73	T
PROVEAN	Benign	-0.83	N
REVEL	Pathogenic	0.82
Sift	Benign	0.13	T
Polyphen		1.0	D
Vest4		0.62
MutPred		0.83		Loss of sheet (P = 0.0315)
MVP		0.96
MPC		0.88
ClinPred		0.61	D
GERP RS		4.6
Varity_R		0.30
gMVP		0.90
Mutation Taster		=2/98	disease causing

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: rs118192168; hg19: chr19-39071043;