rs35180584

Positions:

• chr19-38505358-C-G
• chr19-38505358-C-T

Variant summary

Our verdict is Benign. Variant got -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 serine at codon 2787 of the RYR1 protein, p.(Thr2787Ser). The maximum allele frequency for this variant among the six major gnomAD populations is AFR: 0.029867, 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/CA024914/MONDO:0018493/012

• Frequency:
  • Genomes: 𝑓 0.0088 (20 hom., cov: 32)
  • Exomes 𝑓: 0.0013 (19 hom.)
• Consequence: RYR1 NM_000540.3 missense
• Clinical Significance: Benign reviewed by expert panel B:20 O:1
• Conservation: PhyloP100: 5.60

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]

ACMG classification

Verdict is Benign. Variant got -8 ACMG points.

• BA1: For more information check the summary or visit ClinGen Evidence Repository.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
RYR1	NM_000540.3	c.8360C>G	p.Thr2787Ser	missense_variant	53/106	ENST00000359596.8	NP_000531.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
RYR1	ENST00000359596.8	c.8360C>G	p.Thr2787Ser	missense_variant	53/106	5	NM_000540.3	ENSP00000352608	A2
RYR1	ENST00000355481.8	c.8360C>G	p.Thr2787Ser	missense_variant	53/105	1		ENSP00000347667	P4
RYR1	ENST00000594335.5	c.1814C>G	p.Thr605Ser	missense_variant, NMD_transcript_variant	14/49	1		ENSP00000470927
RYR1	ENST00000599547.6	c.8360C>G	p.Thr2787Ser	missense_variant, NMD_transcript_variant	53/80	2		ENSP00000471601

Frequencies

GnomAD3 genomes AF: 0.00873 AC: 1329 AN: 152166 Hom.: 20 Cov.: 32

Gnomad AFR AF: 0.0290

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00281

Gnomad ASJ AF: 0.0115

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000414

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000441

Gnomad OTH AF: 0.00718

GnomAD3 exomes AF: 0.00291 AC: 724 AN: 249108 Hom.: 9 AF XY: 0.00228 AC XY: 307 AN XY: 134670

Gnomad AFR exome AF: 0.0308

Gnomad AMR exome AF: 0.00282

Gnomad ASJ exome AF: 0.0100

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.0000331

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000346

Gnomad OTH exome AF: 0.000491

GnomAD4 exome AF: 0.00130 AC: 1892 AN: 1460090 Hom.: 19 Cov.: 33 AF XY: 0.00117 AC XY: 851 AN XY: 726194

Gnomad4 AFR exome AF: 0.0304

Gnomad4 AMR exome AF: 0.00285

Gnomad4 ASJ exome AF: 0.00998

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.000186

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.000253

Gnomad4 OTH exome AF: 0.00295

GnomAD4 genome AF: 0.00875 AC: 1333 AN: 152284 Hom.: 20 Cov.: 32 AF XY: 0.00830 AC XY: 618 AN XY: 74464

Gnomad4 AFR AF: 0.0290

Gnomad4 AMR AF: 0.00281

Gnomad4 ASJ AF: 0.0115

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000207

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000441

Gnomad4 OTH AF: 0.00710

Alfa AF: 0.00138 Hom.: 0

Bravo AF: 0.0103

TwinsUK AF: 0.000539 AC: 2

ALSPAC AF: 0.00104 AC: 4

ESP6500AA AF: 0.0293 AC: 129

ESP6500EA AF: 0.000465 AC: 4

ExAC AF: 0.00307 AC: 373

Asia WGS AF: 0.00289 AC: 10 AN: 3478

EpiCase AF: 0.000545

EpiControl AF: 0.000831

ClinVar

Significance: Benign

Submissions summary: Benign:20 Other:1

Revision: reviewed by expert panel

Submissions by phenotype

not provided Benign:5 Other:1

not provided, no classification provided	literature only	Leiden Muscular Dystrophy (RYR1)	-	- -
Benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Aug 01, 2024	RYR1: BS1, BS2 -
Benign, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Oct 14, 2023	- -
Benign, criteria provided, single submitter	clinical testing	Athena Diagnostics	Dec 27, 2018	- -
Likely benign, no assertion criteria provided	clinical testing	Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)	-	- -
Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -

not specified Benign:4

Benign, criteria provided, single submitter	clinical testing	GeneDx	Apr 17, 2017	This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. -
Benign, criteria provided, single submitter	clinical testing	Genetic Services Laboratory, University of Chicago	Feb 08, 2013	- -
Benign, no assertion criteria provided	clinical testing	Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	-	- -
Benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Jul 30, 2015	- -

Malignant hyperthermia, susceptibility to, 1 Benign:3

Benign, criteria provided, single submitter	clinical testing	Color Diagnostics, LLC DBA Color Health	Mar 29, 2019	- -
Likely benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Feb 09, 2018	This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). Publications were found based on this search. The evidence from the literature, in combination with allele frequency data from public databases where available, was sufficient to determine this variant is unlikely to cause disease. Therefore, this variant is classified as likely benign. -
Benign, criteria provided, single submitter	research	Biesecker Lab/Clinical Genomics Section, National Institutes of Health	Jul 01, 2013	- -

RYR1-related disorder Benign:2

Benign, no assertion criteria provided	clinical testing	PreventionGenetics, part of Exact Sciences	May 29, 2019	This variant is classified as benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -
Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 31, 2024	- -

Congenital multicore myopathy with external ophthalmoplegia Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Feb 09, 2018

This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). Publications were found based on this search. The evidence from the literature, in combination with allele frequency data from public databases where available, was sufficient to determine this variant is unlikely to cause disease. Therefore, this variant is classified as likely benign. -

Central core myopathy Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Feb 09, 2018

This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). No publications were found based on this search. Allele frequency data from public databases allowed determination this variant is unlikely to cause disease. Therefore, this variant is classified as likely benign. -

Malignant hyperthermia of anesthesia Benign:1

Benign, reviewed by expert panel

curation

ClinGen Malignant Hyperthermia Susceptibility Variant Curation Expert Panel, ClinGen

Dec 22, 2021

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 serine at codon 2787 of the RYR1 protein, p.(Thr2787Ser). The maximum allele frequency for this variant among the six major gnomAD populations is AFR: 0.029867, 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. -

Neuromuscular disease, congenital, with uniform type 1 fiber Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jun 14, 2016

- -

Malignant hypothermia Benign:1

Benign, criteria provided, single submitter

clinical testing

Genomic Diagnostic Laboratory, Division of Genomic Diagnostics, Children's Hospital of Philadelphia

Jun 26, 2015

- -

Congenital myopathy with fiber type disproportion;C0751951:Central core myopathy;C1840365:King Denborough syndrome;C1850674:Congenital multicore myopathy with external ophthalmoplegia;C2930980:Malignant hyperthermia, susceptibility to, 1 Benign:1

Benign, criteria provided, single submitter

clinical testing

Fulgent Genetics, Fulgent Genetics

May 31, 2022

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.18
BayesDel_addAF	Benign	-0.29	T
BayesDel_noAF	Benign	-0.17
CADD	Benign	21
DANN	Benign	0.90
DEOGEN2	Uncertain	0.66	.;D
Eigen	Benign	0.077
Eigen_PC	Benign	0.18
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Benign	0.82	T;T
MetaRNN	Benign	0.013	T;T
MetaSVM	Uncertain	-0.072	T
MutationAssessor	Benign	1.7	L;L
MutationTaster	Benign	0.99	D;D;D
PrimateAI	Uncertain	0.77	T
PROVEAN	Uncertain	-2.7	D;D
REVEL	Uncertain	0.47
Sift	Benign	0.12	T;T
Polyphen		0.0070	B;B
Vest4		0.62
MutPred		0.78		Gain of disorder (P = 0.0499);Gain of disorder (P = 0.0499);
MVP		0.97
MPC		0.27
ClinPred		0.023	T
GERP RS		4.1
Varity_R		0.34
gMVP		0.31

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

Publications

LitVar

Other links and lift over

dbSNP: rs35180584; hg19: chr19-38995998;