rs976108591

Variant names:

• chr19-38499806-A-G
• rs976108591
• NM_000540.3:c.7199A>G

Variant summary

Our verdict is Uncertain significance. The variant received 2 ACMG points: 2P and 0B. PM1

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 aspartic acid with glycine at codon 2400 of the RYR1 protein, p.(Asp2400Gly). The maximum allele frequency for this variant among the six major gnomAD populations is AFR: 0.000085, a frequency consistent with pathogenicity for MHS. To our knowledge, this variant has not been reported in any individuals with a personal or family history of an MH episode and positive in vitro contracture test (IVCT) or caffeine halothane contracture test (CHCT). 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 (PMID:21118704). A REVEL score of 0.548 supports neither a pathogenic nor a benign status for this variant. This variant has been classified as a Variant of Unknown Significance. Criteria implemented: PM1. LINK:https://erepo.genome.network/evrepo/ui/classification/CA308109644/MONDO:0007783/012

• Frequency:
  • Genomes: 𝑓 0.000013 (0 hom., cov: 32)
  • Exomes 𝑓: 0.000013 (0 hom.)
• Consequence: RYR1 NM_000540.3 missense
• Clinical Significance: Uncertain significance reviewed by expert panel P:1 U:7
• Conservation: PhyloP100: 5.13
• Publications: 1 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: Uncertain_significance. The variant received 2 ACMG points.

• PM1: 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.7199A>G	p.Asp2400Gly	missense	Exon 44 of 106	NP_000531.2	P21817-1
	RYR1	NM_001042723.2		c.7199A>G	p.Asp2400Gly	missense	Exon 44 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.7199A>G	p.Asp2400Gly	missense	Exon 44 of 106	ENSP00000352608.2	P21817-1
	RYR1	ENST00000355481.8	TSL:1	c.7199A>G	p.Asp2400Gly	missense	Exon 44 of 105	ENSP00000347667.3	P21817-2
	RYR1	ENST00000594335.6	TSL:1	n.7199A>G		non_coding_transcript_exon	Exon 44 of 103	ENSP00000470927.2	M0R014

Frequencies

GnomAD3 genomes AF: 0.0000131 AC: 2 AN: 152126 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.0000483

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: 0.00000847 AC: 2 AN: 236076 AF XY: 0.00000773

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000187

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000131 AC: 19 AN: 1452998 Hom.: 0 Cov.: 34 AF XY: 0.0000111 AC XY: 8 AN XY: 723088

African (AFR) AF: 0.00 AC: 0 AN: 33396

American (AMR) AF: 0.00 AC: 0 AN: 44526

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26020

East Asian (EAS) AF: 0.00 AC: 0 AN: 39620

South Asian (SAS) AF: 0.00 AC: 0 AN: 85956

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 46916

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5286

European-Non Finnish (NFE) AF: 0.0000162 AC: 18 AN: 1111158

Other (OTH) AF: 0.0000166 AC: 1 AN: 60120

GnomAD4 genome AF: 0.0000131 AC: 2 AN: 152126 Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0 AN XY: 74300

African (AFR) AF: 0.0000483 AC: 2 AN: 41402

American (AMR) AF: 0.00 AC: 0 AN: 15282

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5190

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

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10622

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

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 68012

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

Alfa AF: 0.0000307 Hom.: 0

Bravo AF: 0.0000151

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: reviewed by expert panel

Pathogenic	VUS	Benign	Condition
-	3	-	not provided (3)
-	2	-	Malignant hyperthermia, susceptibility to, 1 (2)
-	1	-	King Denborough syndrome;C1850674:Congenital multicore myopathy with external ophthalmoplegia;C2930980:Malignant hyperthermia, susceptibility to, 1;C5830701:Central core myopathy (1)
-	1	-	not specified (1)
1	-	-	RYR1-related disorder (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.11
BayesDel_addAF	Pathogenic	0.37	D
BayesDel_noAF	Pathogenic	0.31
CADD	Benign	23
DANN	Uncertain	0.97
DEOGEN2	Benign	0.28	T
Eigen	Benign	-0.38
Eigen_PC	Benign	-0.21
FATHMM_MKL	Uncertain	0.91	D
LIST_S2	Benign	0.70	T
M_CAP	Uncertain	0.26	D
MetaRNN	Benign	0.37	T
MetaSVM	Uncertain	0.17	D
MutationAssessor	Benign	0.090	N
PhyloP100		5.1
PrimateAI	Uncertain	0.61	T
PROVEAN	Benign	-0.080	N
REVEL	Uncertain	0.55
Sift	Benign	1.0	T
Polyphen		0.0040	B
Vest4		0.62
MutPred		0.29		Gain of MoRF binding (P = 0.0212)
MVP		0.94
MPC		0.40
ClinPred		0.63	D
GERP RS		4.0
Varity_R		0.22
gMVP		0.85
Mutation Taster		=0/100	disease causing

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs976108591; hg19: chr19-38990446;