rs34694816

Variant names:

• chr19-38473635-A-G
• rs34694816
• NM_000540.3:c.4024A>G

Variant summary

Our verdict is Benign. The variant received -8 ACMG points: 0P and 8B. BA1

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 Serine with Glycine at codon 1342 of the RYR1 protein, p.(Ser1342Gly). The maximum allele frequency for this variant among the six major gnomAD populations is AFR: 0.1566, which is considered to be too common for a pathogenic variant causing autosomal dominantly inherited MHS, BA1. This variant has been classified as Benign. Criteria implemented: BA1. LINK:https://erepo.genome.network/evrepo/ui/classification/CA024415/MONDO:0007783/012

• Frequency:
  • Genomes: 𝑓 0.044 (468 hom., cov: 31)
  • Exomes 𝑓: 0.0049 (465 hom.)
• Consequence: RYR1 NM_000540.3 missense
• Clinical Significance: Benign reviewed by expert panel B:17 O:1
• Conservation: PhyloP100: 4.27
• Publications: 16 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: Benign. The variant received -8 ACMG points.

• BA1: 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.4024A>G	p.Ser1342Gly	missense	Exon 28 of 106	NP_000531.2	P21817-1
	RYR1	NM_001042723.2		c.4024A>G	p.Ser1342Gly	missense	Exon 28 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.4024A>G	p.Ser1342Gly	missense	Exon 28 of 106	ENSP00000352608.2	P21817-1
	RYR1	ENST00000355481.8	TSL:1	c.4024A>G	p.Ser1342Gly	missense	Exon 28 of 105	ENSP00000347667.3	P21817-2
	RYR1	ENST00000594335.6	TSL:1	n.4024A>G		non_coding_transcript_exon	Exon 28 of 103	ENSP00000470927.2	M0R014

Frequencies

GnomAD3 genomes AF: 0.0437 AC: 6646 AN: 152028 Hom.: 462 Cov.: 31

Gnomad AFR AF: 0.151

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0163

Gnomad ASJ AF: 0.000288

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00124

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.0253

Gnomad NFE AF: 0.000588

Gnomad OTH AF: 0.0364

GnomAD2 exomes AF: 0.0105 AC: 1667 AN: 159276 AF XY: 0.00799

Gnomad AFR exome AF: 0.159

Gnomad AMR exome AF: 0.0100

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000602

Gnomad OTH exome AF: 0.00666

GnomAD4 exome AF: 0.00487 AC: 6859 AN: 1408394 Hom.: 465 Cov.: 33 AF XY: 0.00423 AC XY: 2940 AN XY: 695692

African (AFR) AF: 0.160 AC: 5153 AN: 32220

American (AMR) AF: 0.00986 AC: 356 AN: 36092

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25206

East Asian (EAS) AF: 0.00 AC: 0 AN: 36854

South Asian (SAS) AF: 0.000436 AC: 35 AN: 80356

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 49150

Middle Eastern (MID) AF: 0.0127 AC: 72 AN: 5686

European-Non Finnish (NFE) AF: 0.000479 AC: 519 AN: 1084458

Other (OTH) AF: 0.0124 AC: 724 AN: 58372

GnomAD4 genome AF: 0.0439 AC: 6674 AN: 152144 Hom.: 468 Cov.: 31 AF XY: 0.0428 AC XY: 3183 AN XY: 74394

African (AFR) AF: 0.152 AC: 6300 AN: 41510

American (AMR) AF: 0.0162 AC: 248 AN: 15306

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

East Asian (EAS) AF: 0.00 AC: 0 AN: 5134

South Asian (SAS) AF: 0.000830 AC: 4 AN: 4820

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10610

Middle Eastern (MID) AF: 0.0170 AC: 5 AN: 294

European-Non Finnish (NFE) AF: 0.000588 AC: 40 AN: 67980

Other (OTH) AF: 0.0360 AC: 76 AN: 2110

Alfa AF: 0.0160 Hom.: 43

Bravo AF: 0.0509

ESP6500AA AF: 0.107 AC: 450

ESP6500EA AF: 0.000618 AC: 5

ExAC AF: 0.00977 AC: 1088

Asia WGS AF: 0.0120 AC: 40 AN: 3478

ClinVar

ClinVar submissions

Significance: Benign

Revision: reviewed by expert panel

Pathogenic	VUS	Benign	Condition
-	-	7	not specified (7)
-	-	5	Malignant hyperthermia, susceptibility to, 1 (5)
-	-	2	not provided (3)
-	-	1	Central core myopathy (1)
-	-	1	Congenital multicore myopathy with external ophthalmoplegia (1)
-	-	1	RYR1-related disorder (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.045
BayesDel_addAF	Benign	-0.53	T
BayesDel_noAF	Benign	-0.39
CADD	Benign	21
DANN	Benign	0.86
DEOGEN2	Benign	0.26	T
Eigen	Benign	-0.63
Eigen_PC	Benign	-0.44
FATHMM_MKL	Benign	0.023	N
LIST_S2	Benign	0.25	T
MetaRNN	Benign	0.0016	T
MetaSVM	Benign	-0.91	T
MutationAssessor	Benign	-1.4	N
PhyloP100		4.3
PrimateAI	Benign	0.48	T
PROVEAN	Benign	0.23	N
REVEL	Uncertain	0.29
Sift	Benign	0.47	T
Polyphen		0.0	B
Vest4		0.043
MPC		0.28
ClinPred		0.0024	T
GERP RS		4.0
Varity_R		0.059
gMVP		0.15
Mutation Taster		=100/0	polymorphism (auto)

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: rs34694816; hg19: chr19-38964275;