rs768360593

Variant names:

• chr19-38578015-G-A
• rs768360593
• NM_000540.3:c.14270G>A

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 1P and 1B. PM1_Supporting BP4

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 4757 of the RYR1 protein, p.(Arg4757His). The maximum allele frequency for this variant among the six major gnomAD populations is NFE: .000159, a frequency consistent with pathogenicity for MHS. This variant has been reported in an individual with a personal or family history of an MH episode and 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). However, the high MAF in the NFE population in gnomAD precludes the use of PS4. No functional studies were identified for this variant. This variant resides in a region of RYR1 considered to be a hotspot for pathogenic variants that contribute to MHS, PM1_Sup (PMID:21118704). A REVEL score <0.50 (0.452) supports a benign status for this variant, BP4. This variant has been classified as a Variant of Unknown Significance. Criteria implemented: PM1_Supporting, BP4. LINK:https://erepo.genome.network/evrepo/ui/classification/CA061023/MONDO:0018493/012

• Frequency:
  • Genomes: 𝑓 0.00012 (0 hom., cov: 32)
  • Exomes 𝑓: 0.00017 (0 hom.)
• Consequence: RYR1 NM_000540.3 missense
• Clinical Significance: Uncertain significance reviewed by expert panel U:16 B:1
• Conservation: PhyloP100: 4.44
• Publications: 6 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

Specifications for RYR1 are available in the ClinGen Criteria Specification Registry and recommended for reference when assigning criteria.

Our verdict: Uncertain_significance. The variant received 0 ACMG points.

• PM1: For more information check the summary or visit ClinGen Evidence Repository.
• BP4: 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.14270G>A	p.Arg4757His	missense	Exon 98 of 106	NP_000531.2	P21817-1
	RYR1	NM_001042723.2		c.14255G>A	p.Arg4752His	missense	Exon 97 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.14270G>A	p.Arg4757His	missense	Exon 98 of 106	ENSP00000352608.2	P21817-1
	RYR1	ENST00000355481.8	TSL:1	c.14255G>A	p.Arg4752His	missense	Exon 97 of 105	ENSP00000347667.3	P21817-2
	RYR1	ENST00000594335.6	TSL:1	n.*4980G>A		non_coding_transcript_exon	Exon 95 of 103	ENSP00000470927.2	M0R014

Frequencies

GnomAD3 genomes AF: 0.000125 AC: 19 AN: 152140 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.0000724

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: 0.000235

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.0000996 AC: 25 AN: 251108 AF XY: 0.0000516

Gnomad AFR exome AF: 0.000123

Gnomad AMR exome AF: 0.0000579

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000159

Gnomad OTH exome AF: 0.000326

GnomAD4 exome AF: 0.000170 AC: 249 AN: 1461862 Hom.: 0 Cov.: 32 AF XY: 0.000149 AC XY: 108 AN XY: 727228

African (AFR) AF: 0.0000597 AC: 2 AN: 33480

American (AMR) AF: 0.0000671 AC: 3 AN: 44722

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26134

East Asian (EAS) AF: 0.00 AC: 0 AN: 39696

South Asian (SAS) AF: 0.0000232 AC: 2 AN: 86256

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53406

Middle Eastern (MID) AF: 0.000693 AC: 4 AN: 5768

European-Non Finnish (NFE) AF: 0.000198 AC: 220 AN: 1112006

Other (OTH) AF: 0.000298 AC: 18 AN: 60394

GnomAD4 genome AF: 0.000125 AC: 19 AN: 152140 Hom.: 0 Cov.: 32 AF XY: 0.000108 AC XY: 8 AN XY: 74322

African (AFR) AF: 0.0000724 AC: 3 AN: 41428

American (AMR) AF: 0.00 AC: 0 AN: 15268

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

East Asian (EAS) AF: 0.00 AC: 0 AN: 5192

South Asian (SAS) AF: 0.00 AC: 0 AN: 4830

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10618

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

European-Non Finnish (NFE) AF: 0.000235 AC: 16 AN: 68014

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

Alfa AF: 0.000116 Hom.: 0

Bravo AF: 0.000117

ExAC AF: 0.000123 AC: 15

EpiCase AF: 0.000273

EpiControl AF: 0.000296

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: reviewed by expert panel

Pathogenic	VUS	Benign	Condition
-	9	-	not provided (9)
-	2	-	Malignant hyperthermia, susceptibility to, 1 (2)
-	1	-	Central core myopathy (1)
-	1	-	Congenital multicore myopathy with external ophthalmoplegia (1)
-	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)
-	1	-	Malignant hyperthermia of anesthesia (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	0.11
BayesDel_addAF	Benign	-0.017	T
BayesDel_noAF	Uncertain	0.0
CADD	Benign	23
DANN	Benign	0.97
DEOGEN2	Uncertain	0.47	T
Eigen	Uncertain	0.31
Eigen_PC	Uncertain	0.35
FATHMM_MKL	Benign	0.63	D
LIST_S2	Benign	0.86	D
M_CAP	Uncertain	0.21	D
MetaRNN	Benign	0.33	T
MetaSVM	Uncertain	0.44	D
MutationAssessor	Benign	0.90	L
PhyloP100		4.4
PrimateAI	Benign	0.44	T
PROVEAN	Benign	-2.3	N
REVEL	Uncertain	0.45
Sift	Benign	0.035	D
Polyphen		0.99	D
Vest4		0.34
MVP		0.99
MPC		0.71
ClinPred		0.12	T
GERP RS		4.0
Varity_R		0.059
gMVP		0.34
Mutation Taster		=46/54	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: rs768360593; hg19: chr19-39068655; COSMIC: COSV62103766;