rs199738299

Variant names:

• chr19-38516167-A-G
• rs199738299
• NM_000540.3:c.9635A>G
• RYR1 p.Glu3212Gly

Variant summary

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

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 glutamic acid with glycine at codon 3212 of the RYR1 protein, p.(Glu3212Gly). The maximum allele frequency for this variant among the six major gnomAD populations is NFE: 0.0005609, 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 does not reside in a hotspot for pathogenic variants that contribute to MHS. A REVEL score of 0.624 supports neither a pathogenic nor a benign status for this variant. This variant has been classified as a Variant of Unknown Significance. No criteria implemented. LINK:https://erepo.genome.network/evrepo/ui/classification/CA073912/MONDO:0018493/012

• Frequency:
  • Genomes: 𝑓 0.00036 (0 hom., cov: 32)
  • Exomes 𝑓: 0.00035 (2 hom.)
• Consequence: RYR1 NM_000540.3 missense
• Clinical Significance: Uncertain significance reviewed by expert panel U:14 B:3
• Conservation: PhyloP100: 6.18
• Publications: 4 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: ClinGen, Ambry Genetics, Genomics England PanelApp, Labcorp Genetics (formerly Invitae), PanelApp Australia
• 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: Genomics England PanelApp, G2P
• central core myopathy

  Inheritance: AD, AR Classification: STRONG, SUPPORTIVE Submitted by: Orphanet, Genomics England PanelApp, Labcorp Genetics (formerly Invitae)
• 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.

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.9635A>G	p.Glu3212Gly	missense	Exon 65 of 106	NP_000531.2	P21817-1
	RYR1	NM_001042723.2		c.9635A>G	p.Glu3212Gly	missense	Exon 65 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.9635A>G	p.Glu3212Gly	missense	Exon 65 of 106	ENSP00000352608.2	P21817-1
	RYR1	ENST00000355481.8	TSL:1	c.9635A>G	p.Glu3212Gly	missense	Exon 65 of 105	ENSP00000347667.3	P21817-2
	RYR1	ENST00000594335.6	TSL:1	n.*378A>G		non_coding_transcript_exon	Exon 64 of 103	ENSP00000470927.2	M0R014

Frequencies

GnomAD3 genomes AF: 0.000361 AC: 55 AN: 152200 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.0000965

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0000654

Gnomad ASJ AF: 0.000288

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.000282

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000647

Gnomad OTH AF: 0.000955

GnomAD2 exomes AF: 0.000261 AC: 45 AN: 172580 AF XY: 0.000185

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.000114

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.000124

Gnomad NFE exome AF: 0.000570

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.000345 AC: 487 AN: 1410940 Hom.: 2 Cov.: 31 AF XY: 0.000340 AC XY: 237 AN XY: 696892

African (AFR) AF: 0.0000310 AC: 1 AN: 32224

American (AMR) AF: 0.000134 AC: 5 AN: 37318

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25320

East Asian (EAS) AF: 0.00 AC: 0 AN: 36828

South Asian (SAS) AF: 0.00 AC: 0 AN: 80006

European-Finnish (FIN) AF: 0.000121 AC: 6 AN: 49486

Middle Eastern (MID) AF: 0.000179 AC: 1 AN: 5572

European-Non Finnish (NFE) AF: 0.000428 AC: 465 AN: 1085658

Other (OTH) AF: 0.000154 AC: 9 AN: 58528

GnomAD4 genome AF: 0.000361 AC: 55 AN: 152200 Hom.: 0 Cov.: 32 AF XY: 0.000363 AC XY: 27 AN XY: 74366

African (AFR) AF: 0.0000965 AC: 4 AN: 41446

American (AMR) AF: 0.0000654 AC: 1 AN: 15282

Ashkenazi Jewish (ASJ) AF: 0.000288 AC: 1 AN: 3468

East Asian (EAS) AF: 0.00 AC: 0 AN: 5194

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

European-Finnish (FIN) AF: 0.000282 AC: 3 AN: 10622

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

European-Non Finnish (NFE) AF: 0.000647 AC: 44 AN: 68036

Other (OTH) AF: 0.000955 AC: 2 AN: 2094

Alfa AF: 0.000481 Hom.: 0

Bravo AF: 0.000359

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: reviewed by expert panel

Pathogenic	VUS	Benign	Condition
-	4	-	Malignant hyperthermia, susceptibility to, 1 (4)
-	4	-	not provided (4)
-	2	-	Congenital multicore myopathy with external ophthalmoplegia (2)
-	-	1	Central core myopathy (1)
-	1	-	Congenital myopathy with fiber type disproportion (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	-	not specified (1)
-	-	1	RYR1-related disorder (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.14
BayesDel_addAF	Benign	-0.055	T
BayesDel_noAF	Uncertain	0.030
CADD	Benign	23
DANN	Uncertain	0.99
DEOGEN2	Uncertain	0.72	D
Eigen	Uncertain	0.43
Eigen_PC	Uncertain	0.46
FATHMM_MKL	Uncertain	0.96	D
LIST_S2	Uncertain	0.87	D
M_CAP	Uncertain	0.22	D
MetaRNN	Uncertain	0.49	T
MetaSVM	Uncertain	0.45	D
MutationAssessor	Uncertain	2.2	M
PhyloP100		6.2
PrimateAI	Uncertain	0.53	T
PROVEAN	Uncertain	-3.9	D
REVEL	Uncertain	0.62
Sift	Uncertain	0.014	D
Varity_R		0.29
gMVP		0.53
Mutation Taster		=15/85	disease causing

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.37		Details are displayed if max score is > 0.2
DS_DG_spliceai		0.37		Position offset: 0

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

MaxEntScan Visualizer can be used to analyze the impact of this mutation on the neighboring sequence.

Other links and lift over

dbSNP: rs199738299;

hg19: chr19-39006807;