rs73933023

Variant names:

• chr19-38566975-C-T
• rs73933023
• NM_000540.3:c.13502C>T

Your query was ambiguous. Multiple possible variants found:

• chr19-38566975-C-T
• chr19-38566975-C-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 Proline with Leucine at codon 4501 of the RYR1 protein, p.(Pro4501Leu). The maximum allele frequency for this variant among the six major gnomAD populations is AFR: 0.0181, 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/CA059964/MONDO:0007783/012

• Frequency:
  • Genomes: 𝑓 0.0057 (2 hom., cov: 31)
  • Exomes 𝑓: 0.0013 (12 hom.)
• Consequence: RYR1 NM_000540.3 missense
• Clinical Significance: Benign reviewed by expert panel B:16
• Conservation: PhyloP100: 1.42
• Publications: 11 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: 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.13502C>T	p.Pro4501Leu	missense	Exon 92 of 106	NP_000531.2	P21817-1
	RYR1	NM_001042723.2		c.13487C>T	p.Pro4496Leu	missense	Exon 91 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.13502C>T	p.Pro4501Leu	missense	Exon 92 of 106	ENSP00000352608.2	P21817-1
	RYR1	ENST00000355481.8	TSL:1	c.13487C>T	p.Pro4496Leu	missense	Exon 91 of 105	ENSP00000347667.3	P21817-2
	RYR1	ENST00000594335.6	TSL:1	n.*4212C>T		non_coding_transcript_exon	Exon 89 of 103	ENSP00000470927.2	M0R014

Frequencies

GnomAD3 genomes AF: 0.00561 AC: 853 AN: 152088 Hom.: 2 Cov.: 31

Gnomad AFR AF: 0.0180

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00223

Gnomad ASJ AF: 0.000864

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00310

Gnomad FIN AF: 0.0000943

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000735

Gnomad OTH AF: 0.00288

GnomAD2 exomes AF: 0.00213 AC: 461 AN: 216354 AF XY: 0.00186

Gnomad AFR exome AF: 0.0183

Gnomad AMR exome AF: 0.00168

Gnomad ASJ exome AF: 0.000852

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.0000551

Gnomad NFE exome AF: 0.000694

Gnomad OTH exome AF: 0.00165

GnomAD4 exome AF: 0.00128 AC: 1845 AN: 1444556 Hom.: 12 Cov.: 32 AF XY: 0.00126 AC XY: 900 AN XY: 716860

African (AFR) AF: 0.0193 AC: 642 AN: 33228

American (AMR) AF: 0.00183 AC: 77 AN: 42106

Ashkenazi Jewish (ASJ) AF: 0.000543 AC: 14 AN: 25786

East Asian (EAS) AF: 0.0000256 AC: 1 AN: 39086

South Asian (SAS) AF: 0.00271 AC: 226 AN: 83338

European-Finnish (FIN) AF: 0.0000768 AC: 4 AN: 52080

Middle Eastern (MID) AF: 0.00354 AC: 20 AN: 5648

European-Non Finnish (NFE) AF: 0.000689 AC: 760 AN: 1103608

Other (OTH) AF: 0.00169 AC: 101 AN: 59676

GnomAD4 genome AF: 0.00565 AC: 860 AN: 152206 Hom.: 2 Cov.: 31 AF XY: 0.00556 AC XY: 414 AN XY: 74410

African (AFR) AF: 0.0181 AC: 751 AN: 41532

American (AMR) AF: 0.00222 AC: 34 AN: 15282

Ashkenazi Jewish (ASJ) AF: 0.000864 AC: 3 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5166

South Asian (SAS) AF: 0.00311 AC: 15 AN: 4830

European-Finnish (FIN) AF: 0.0000943 AC: 1 AN: 10606

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.000735 AC: 50 AN: 68008

Other (OTH) AF: 0.00285 AC: 6 AN: 2104

Alfa AF: 0.00504 Hom.: 12

Bravo AF: 0.00626

TwinsUK AF: 0.00 AC: 0

ALSPAC AF: 0.00156 AC: 6

ESP6500AA AF: 0.0157 AC: 69

ESP6500EA AF: 0.000931 AC: 8

ExAC AF: 0.00245 AC: 296

Asia WGS AF: 0.00202 AC: 7 AN: 3478

ClinVar

ClinVar submissions

Significance: Benign

Revision: reviewed by expert panel

Pathogenic	VUS	Benign	Condition
-	-	4	Malignant hyperthermia, susceptibility to, 1 (4)
-	-	4	not provided (4)
-	-	2	not specified (2)
-	-	2	RYR1-related disorder (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	Neuromuscular disease, congenital, with uniform type 1 fiber (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.15
BayesDel_addAF	Benign	-0.29	T
BayesDel_noAF	Benign	-0.18
CADD	Benign	19
DANN	Benign	0.80
DEOGEN2	Pathogenic	0.83	D
Eigen	Benign	-0.14
Eigen_PC	Benign	-0.19
FATHMM_MKL	Uncertain	0.91	D
LIST_S2	Uncertain	0.86	D
MetaRNN	Benign	0.0088	T
MetaSVM	Uncertain	-0.069	T
MutationAssessor	Uncertain	2.2	M
PhyloP100		1.4
PrimateAI	Uncertain	0.57	T
PROVEAN	Uncertain	-3.6	D
REVEL	Uncertain	0.42
Sift	Benign	0.059	T
Polyphen		0.94	P
Vest4		0.36
MVP		0.84
MPC		0.58
ClinPred		0.033	T
GERP RS		3.6
Varity_R		0.15
gMVP		0.56
Mutation Taster		=95/5	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
Splicevardb		2.0
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: rs73933023; hg19: chr19-39057615;