rs587784372

Variant names:

• chr19-38565215-C-T
• rs587784372
• NM_000540.3:c.12881C>T

Your query was ambiguous. Multiple possible variants found:

• chr19-38565215-C-T
• chr19-38565215-C-A

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 Threonine with Methionine at codon 4294 of the RYR1 protein, p.(Thr4294Met). The maximum allele frequency for this variant among the six major gnomAD populations is AFR: 0.0193, 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/CA024017/MONDO:0007783/012

• Frequency:
  • Genomes: 𝑓 0.0043 (8 hom., cov: 31)
  • Exomes 𝑓: 0.00046 (0 hom.)
• Consequence: RYR1 NM_000540.3 missense
• Clinical Significance: Benign reviewed by expert panel U:6 B:6
• Conservation: PhyloP100: 0.974
• 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

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.12881C>T	p.Thr4294Met	missense	Exon 91 of 106	NP_000531.2	P21817-1
	RYR1	NM_001042723.2		c.12866C>T	p.Thr4289Met	missense	Exon 90 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.12881C>T	p.Thr4294Met	missense	Exon 91 of 106	ENSP00000352608.2	P21817-1
	RYR1	ENST00000355481.8	TSL:1	c.12866C>T	p.Thr4289Met	missense	Exon 90 of 105	ENSP00000347667.3	P21817-2
	RYR1	ENST00000594335.6	TSL:1	n.*3591C>T		non_coding_transcript_exon	Exon 88 of 103	ENSP00000470927.2	M0R014

Frequencies

GnomAD3 genomes AF: 0.00433 AC: 633 AN: 146188 Hom.: 8 Cov.: 31

Gnomad AFR AF: 0.0147

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000952

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00645

Gnomad NFE AF: 0.000213

Gnomad OTH AF: 0.00199

GnomAD2 exomes AF: 0.00336 AC: 1 AN: 298 AF XY: 0.00602

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00350

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.000456 AC: 386 AN: 846942 Hom.: 0 Cov.: 30 AF XY: 0.000440 AC XY: 173 AN XY: 392846

African (AFR) AF: 0.0179 AC: 286 AN: 16022

American (AMR) AF: 0.00 AC: 0 AN: 1490

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 5424

East Asian (EAS) AF: 0.00 AC: 0 AN: 4048

South Asian (SAS) AF: 0.00 AC: 0 AN: 17424

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 1704

Middle Eastern (MID) AF: 0.00120 AC: 2 AN: 1670

European-Non Finnish (NFE) AF: 0.0000973 AC: 75 AN: 771090

Other (OTH) AF: 0.000819 AC: 23 AN: 28070

GnomAD4 genome AF: 0.00434 AC: 635 AN: 146294 Hom.: 8 Cov.: 31 AF XY: 0.00418 AC XY: 298 AN XY: 71230

African (AFR) AF: 0.0147 AC: 601 AN: 40838

American (AMR) AF: 0.000950 AC: 14 AN: 14732

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3388

East Asian (EAS) AF: 0.00 AC: 0 AN: 5090

South Asian (SAS) AF: 0.00 AC: 0 AN: 4798

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 8408

Middle Eastern (MID) AF: 0.00690 AC: 2 AN: 290

European-Non Finnish (NFE) AF: 0.000213 AC: 14 AN: 65802

Other (OTH) AF: 0.00196 AC: 4 AN: 2036

Alfa AF: 0.000716 Hom.: 0

ClinVar

ClinVar submissions

Significance: Benign

Revision: reviewed by expert panel

Pathogenic	VUS	Benign	Condition
-	2	2	not provided (4)
-	1	1	Malignant hyperthermia, susceptibility to, 1 (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	-	Inborn genetic diseases (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.30
BayesDel_addAF	Benign	-0.12	T
BayesDel_noAF	Uncertain	0.070
CADD	Benign	6.4
DANN	Benign	0.95
DEOGEN2	Benign	0.29	T
Eigen	Benign	-1.1
Eigen_PC	Benign	-1.2
FATHMM_MKL	Benign	0.050	N
LIST_S2	Benign	0.27	T
M_CAP	Pathogenic	0.99	D
MetaRNN	Benign	0.082	T
MetaSVM	Uncertain	-0.21	T
MutationAssessor	Benign	0.55	N
PhyloP100		0.97
PrimateAI	Pathogenic	0.91	D
PROVEAN	Benign	0.090	N
REVEL	Uncertain	0.53
Sift	Benign	0.23	T
Polyphen		0.17	B
Vest4		0.15
MutPred		0.78		Loss of phosphorylation at T4294 (P = 0.0199)
MVP		0.84
MPC		0.76
ClinPred		0.045	T
GERP RS		-1.4
PromoterAI		0.021	Neutral
Varity_R		0.016
gMVP		0.26
Mutation Taster		=93/7	polymorphism

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: rs587784372; hg19: chr19-39055855;