chr19-38475335-A-G

Position:

chr19-38475335-A-G

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 lysine with arginine at codon 1393 of the RYR1 protein, p.(Lys1393Arg). The maximum allele frequency for this variant among the six major gnomAD populations is NFE: 0.0046, 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/CA024433/MONDO:0018493/012

Frequency

Genomes: 𝑓 0.0028 ( 1 hom., cov: 32)

Exomes 𝑓: 0.0035 ( 19 hom. )

Consequence

RYR1
NM_000540.3 missense

Scores

Clinical Significance

Benign reviewed by expert panel U:5B:19

Conservation

PhyloP100: 4.86

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/exons	MANE	Protein	UniProt
RYR1	NM_000540.3 linkuse as main transcript	c.4178A>G	p.Lys1393Arg	missense_variant	29/106	ENST00000359596.8	NP_000531.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
RYR1	ENST00000359596.8 linkuse as main transcript	c.4178A>G	p.Lys1393Arg	missense_variant	29/106	5	NM_000540.3	ENSP00000352608	A2	P21817-1
RYR1	ENST00000355481.8 linkuse as main transcript	c.4178A>G	p.Lys1393Arg	missense_variant	29/105	1		ENSP00000347667	P4	P21817-2
RYR1	ENST00000599547.6 linkuse as main transcript	c.4178A>G	p.Lys1393Arg	missense_variant, NMD_transcript_variant	29/80	2		ENSP00000471601

Frequencies

GnomAD3 genomes

AF:

0.00277

AC:

422

AN:

152132

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00109

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00170

Gnomad ASJ

AF:

0.000288

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00188

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00478

Gnomad OTH

AF:

0.00239

GnomAD3 exomes

AF:

0.00273

AC:

617

AN:

225862

Hom.:

AF XY:

0.00269

AC XY:

327

AN XY:

121580

show subpopulations

Gnomad AFR exome

AF:

0.00128

Gnomad AMR exome

AF:

0.00227

Gnomad ASJ exome

AF:

0.000105

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00225

Gnomad NFE exome

AF:

0.00469

Gnomad OTH exome

AF:

0.00194

GnomAD4 exome

AF:

0.00353

AC:

5110

AN:

1447116

Hom.:

Cov.:

AF XY:

0.00344

AC XY:

2472

AN XY:

718420

show subpopulations

Gnomad4 AFR exome

AF:

0.000904

Gnomad4 AMR exome

AF:

0.00209

Gnomad4 ASJ exome

AF:

0.000116

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00210

Gnomad4 NFE exome

AF:

0.00428

Gnomad4 OTH exome

AF:

0.00245

GnomAD4 genome

AF:

0.00277

AC:

421

AN:

152250

Hom.:

Cov.:

AF XY:

0.00222

AC XY:

165

AN XY:

74444

show subpopulations

Gnomad4 AFR

AF:

0.00108

Gnomad4 AMR

AF:

0.00170

Gnomad4 ASJ

AF:

0.000288

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00188

Gnomad4 NFE

AF:

0.00476

Gnomad4 OTH

AF:

0.00237

Alfa

AF:

0.00406

Hom.:

Bravo

AF:

0.00304

TwinsUK

AF:

0.00431

AC:

ALSPAC

AF:

0.00493

AC:

ESP6500AA

AF:

0.00136

AC:

ESP6500EA

AF:

0.00582

AC:

ExAC

AF:

0.00245

AC:

297

Asia WGS

AF:

0.000577

AC:

AN:

3478

ClinVar

Significance: Benign

Submissions summary: Uncertain:5Benign:19

Revision: reviewed by expert panel

LINK: link

Submissions by phenotype

not provided

Uncertain:4Benign:6

Uncertain significance, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Jun 03, 2015	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Mayo Clinic Laboratories, Mayo Clinic	Dec 01, 2021	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics	Feb 22, 2017	- -
Likely benign, criteria provided, single submitter	clinical testing	GeneDx	Oct 06, 2020	Reported previously in individuals with features of RYR1-related disorders, but familial segregation information was not always included and some individuals were noted to have other potentially causative variants (Vukcevic et al., 2010; Dlamini et al., 2013; Loseth et al., 2013; Gillies et al., 2015); In silico analysis, which includes protein predictors and evolutionary conservation, supports that this variant does not alter protein structure/function; This variant is associated with the following publications: (PMID: 26332594, 20142353, 27153395, 25637381, 25985138, 23329375, 24195946, 25735680, 23628358, 28496993, 30788618, 30916033) -
Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Jun 01, 2024	RYR1: BS2 -
Likely benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Likely benign, no assertion criteria provided	clinical testing	Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	-	- -
Likely benign, no assertion criteria provided	clinical testing	Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	-	- -
Likely benign, no assertion criteria provided	clinical testing	Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)	-	- -
Uncertain significance, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Apr 01, 2022	The RYR1 c.4178A>G, p.Lys1393Arg variant (rs137933390) has been identified in several individuals with clinical suspicion for malignant hyperthermia susceptibility (MHS) syndrome or other related myopathy (Bick 2017, Gillies 2015, Loseth 2013, Vukcevic 2010). Additionally, a cell line isolated from an MHS patient showed increased sensitivity to 4-chloro-m-cresol (Vukcevic 2010). However, variant has been identified at high allele frequency in several control populations, and is found in the non-Finnish European population with an allele frequency of 0.46% (537/ 115776 alleles, including 2 homozygotes) in the Genome Aggregation Database. Due to this high population frequency, the ClinGen Malignant Hyperthermia Susceptibility Variant Curation Expert Panel considers this variant benign with respect to autosomal dominant MHS (ClinVar Variation ID: 93269). However, this population frequency alone is not high enough alone to rule out a potential role with respect to the recessive myopathies associated with loss of function variation in RYR1. Therefore, while considered benign for MHS specifically, the overall classification of this variant is uncertain. References: Bick D et al. Successful Application of Whole Genome Sequencing in a Medical Genetics Clinic. J Pediatr Genet. 2017 Jun;6(2):61-76. PMID: 28496993 Gillies RL et al. Analysis of the entire ryanodine receptor type 1 and alpha 1 subunit of the dihydropyridine receptor (CACNA1S) coding regions for variants associated with malignant hyperthermia in Australian families. Anaesth Intensive Care. 2015 Mar;43(2):157-66. PMID: 25735680. Loseth S et al. A novel late-onset axial myopathy associated with mutations in the skeletal muscle ryanodine receptor (RYR1) gene. J Neurol. 2013 Jun;260(6):1504-10. PMID: 23329375. Vukcevic M et al. Functional properties of RYR1 mutations identified in Swedish patients with malignant hyperthermia and central core disease. Anesth Analg. 2010 Jul;111(1):185-90. PMID: 20142353. -

Malignant hyperthermia, susceptibility to, 1

Benign:5

Likely benign, criteria provided, single submitter	clinical testing	Color Diagnostics, LLC DBA Color Health	Jul 12, 2022	- -
Likely benign, no assertion criteria provided	research	CSER _CC_NCGL, University of Washington	Jun 01, 2014	- -
Benign, criteria provided, single submitter	research	Biesecker Lab/Clinical Genomics Section, National Institutes of Health	Jul 01, 2013	- -
Likely benign, criteria provided, single submitter	clinical testing	Molecular Genetics, Royal Melbourne Hospital	Mar 30, 2023	This sequence change is predicted to replace lysine with arginine at codon 1393 of the RYR1 protein (p.(Lys1393Arg)). The lysine residue is conserved (100 vertebrates, UCSC), and there is a small physicochemical difference between lysine and arginine. It is not in an annotated domain. The variant is present in a large population cohort at a frequency of 0.46% in the European non-Finnish population (rs137933390, gnomAD v2.1.1 and v3.0). In comparison, the variant was present at a frequency of 0.46% in a cohort of individuals with malignant hyperthermia susceptibility (PMID: 24195946). This variant has been seen in at least 13 individuals with malignant hyperthermia susceptibility, including some individuals where another RYR1 variant was identified (PMID: 24195946, 19346234, 25960145, 23558838, 24433488, 25735680, 28326467), as well as being present in individuals with myopathy, rhabdomyolysis and exertional heat stroke (PMID: 22473935, 23628358, 23329375, 26565425, 28496993), although several authors acknowledge the high population frequency and comment that the variant is unlikely to be pathogenic. This variant has been shown not to segregate with the malignant hyperthermia susceptibility phenotype in two unrelated families, although the pedigrees have not been confirmed (PMID: 25658027). It has been reported in at least three further individuals without malignant hyperthermia (PMID: 25614869). Functional data from a lymphoblastoid cell line demonstrated 4-chloro-m-cresol induced calcium release at a lower concentration, however it is unclear whether this is a true reflection of the skeletal myocyte (PMID: 20142353). Multiple lines of computational evidence have conflicting predictions for the missense substitution (4/6 algorithms predict benign/neutral effect, 1/6 algorithms predict deleterious effect, 1/6 algorithms have an unknown prediction). Based on the classification guidelines RMH Modified ACMG Guidelines v1.3.0, this variant is classified as LIKELY BENIGN. The following criteria are met: BS1, BP5. -
Benign, criteria provided, single submitter	clinical testing	Mendelics	May 28, 2019	- -

not specified

Uncertain:1Benign:1

Uncertain significance, criteria provided, single submitter	clinical testing	Athena Diagnostics	Apr 21, 2017	- -
Benign, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, University Medical Center Utrecht	-	- -

RYR1-related disorder

Benign:2

Likely benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Feb 01, 2024	- -
Likely benign, no assertion criteria provided	clinical testing	PreventionGenetics, part of Exact Sciences	Jul 25, 2024	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). -

Malignant hyperthermia of anesthesia

Benign:2

Benign, reviewed by expert panel	curation	ClinGen Malignant Hyperthermia Susceptibility Variant Curation Expert Panel, ClinGen	Jan 03, 2022	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 lysine with arginine at codon 1393 of the RYR1 protein, p.(Lys1393Arg). The maximum allele frequency for this variant among the six major gnomAD populations is NFE: 0.0046, 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. -
Likely benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Jun 14, 2016	- -

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). 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. -

Central core myopathy

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Feb 09, 2018

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

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.077

BayesDel_addAF

Benign

-0.072

BayesDel_noAF

Uncertain

0.13

CADD

Benign

DANN

Uncertain

1.0

DEOGEN2

Benign

0.32

.;T

Eigen

Benign

-0.056

Eigen_PC

Benign

0.090

FATHMM_MKL

Uncertain

0.94

LIST_S2

Benign

0.83

T;T

M_CAP

Benign

0.084

MetaRNN

Benign

0.011

T;T

MetaSVM

Uncertain

0.44

MutationAssessor

Benign

1.2

L;L

MutationTaster

Benign

0.57

D;D;D

PrimateAI

Uncertain

0.69

PROVEAN

Benign

-0.30

N;N

REVEL

Uncertain

0.56

Sift

Benign

0.34

T;T

Polyphen

0.39

B;B

Vest4

0.56

MVP

0.98

MPC

0.37

ClinPred

0.017

GERP RS

4.6

Varity_R

0.072

gMVP

0.54

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.060

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