19-38565215-C-T

Variant names:

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 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

Scores

Clinical Significance

Benign reviewed by expert panel U:6B:6

Conservation

PhyloP100: 0.974

Variant links:

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 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

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 rank	MANE	Protein	UniProt
RYR1	NM_000540.3 link	c.12881C>T	p.Thr4294Met	missense_variant	Exon 91 of 106	ENST00000359596.8	NP_000531.2	P21817-1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
RYR1	ENST00000359596.8 link	c.12881C>T	p.Thr4294Met	missense_variant	Exon 91 of 106	5	NM_000540.3	ENSP00000352608.2		P21817-1

Frequencies

GnomAD3 genomes

AF:

0.00433

AC:

633

AN:

146188

Hom.:

Cov.:

show subpopulations

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

GnomAD3 exomes

AF:

0.00336

AC:

AN:

298

Hom.:

AF XY:

0.00602

AC XY:

AN XY:

166

show subpopulations

Gnomad SAS exome

AF:

0.00

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.:

Cov.:

AF XY:

0.000440

AC XY:

173

AN XY:

392846

show subpopulations

Gnomad4 AFR exome

AF:

0.0179

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.0000973

Gnomad4 OTH exome

AF:

0.000819

GnomAD4 genome

AF:

0.00434

AC:

635

AN:

146294

Hom.:

Cov.:

AF XY:

0.00418

AC XY:

298

AN XY:

71230

show subpopulations

Gnomad4 AFR

AF:

0.0147

Gnomad4 AMR

AF:

0.000950

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.000213

Gnomad4 OTH

AF:

0.00196

Alfa

AF:

0.000716

Hom.:

ClinVar

Significance: Benign

Submissions summary: Uncertain:6Benign:6

Revision: reviewed by expert panel

LINK: link

Submissions by phenotype

not provided

Uncertain:2Benign:2

Jan 23, 2014

Genetic Services Laboratory, University of Chicago

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Sep 27, 2017

Eurofins Ntd Llc (ga)

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Jul 22, 2020

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant is associated with the following publications: (PMID: 19807743, 23476141, 28326467, 27663056) -

Dec 01, 2023

CeGaT Center for Human Genetics Tuebingen

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

RYR1: PP3, BS1 -

Malignant hyperthermia, susceptibility to, 1

Uncertain:1Benign:1

Mar 17, 2021

ClinGen Malignant Hyperthermia Susceptibility Variant Curation Expert Panel, ClinGen

Significance: Benign

Review Status: reviewed by expert panel

Collection Method: curation

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. -

Jan 28, 2019

Illumina Laboratory Services, Illumina

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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. However, the evidence from the literature, in combination with allele frequency data from public databases where available, was not sufficient to rule this variant in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance. -

RYR1-related disorder

Benign:2

Apr 13, 2023

PreventionGenetics, part of Exact Sciences

Significance: Likely benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Jan 31, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Congenital multicore myopathy with external ophthalmoplegia

Uncertain:1

Jan 28, 2019

Illumina Laboratory Services, Illumina

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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 did not allow this variant to be ruled in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance. -

Inborn genetic diseases

Uncertain:1

Mar 04, 2016

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Central core myopathy

Uncertain:1

Jan 28, 2019

Illumina Laboratory Services, Illumina

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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 did not allow this variant to be ruled in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance. -

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

Benign:1

Apr 29, 2022

Fulgent Genetics, Fulgent Genetics

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.30

BayesDel_addAF

Benign

-0.12

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

LIST_S2

Benign

0.27

T;T

M_CAP

Pathogenic

0.99

MetaRNN

Benign

0.082

T;T

MetaSVM

Uncertain

-0.21

MutationAssessor

Benign

0.55

.;N

PrimateAI

Pathogenic

0.91

PROVEAN

Benign

0.090

N;N

REVEL

Uncertain

0.53

Sift

Benign

0.23

T;T

Polyphen

0.17

B;B

Vest4

0.15

MutPred

0.78

.;Loss of phosphorylation at T4294 (P = 0.0199);

MVP

0.84

MPC

0.76

ClinPred

0.045

GERP RS

-1.4

Varity_R

0.016

gMVP

0.26

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over