rs146429605

Positions:

chr19-38483293-A-G

Variant summary

Our verdict is Likely benign. Variant got -4 ACMG points: 0P and 4B. BS1

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 Isoleucine with Valine at codon 1571 of the RYR1 protein, p.(Ile1571Val). The maximum allele frequency for this variant among the six major gnomAD populations is NFE: 0.0014, this is considered to be more common than expected for a pathogenic variant causing autosomal dominantly inherited MHS, BS1. This variant has been reported in five unrelated individuals who have a personal or family history of a malignant hyperthermia reaction, all of these individuals had a positive in vitro contracture test (IVCT) or caffeine halothane contracture test (CHCT) result (if the proband was unavailable for testing, a positive diagnostic test result in a mutation-positive relative was counted), (PMID:25958340, PMID:20681998, PMID:25658027, PMID:25735680). However, the high MAF in the NFE population in gnomAD precludes the use of PS4. No functional studies were identified for this variant. This variant does not reside in a hotspot for pathogenic variants that contribute to MHS. A REVEL score of 0.56 supports neither a pathogenic nor a benign status for this variant. Based on using Bayes to combine criteria this variant is assessed as Likely Benign, (PMID:29300386). Criteria implemented: BS1. LINK:https://erepo.genome.network/evrepo/ui/classification/CA024455/MONDO:0007783/012

Frequency

Genomes: 𝑓 0.0011 ( 1 hom., cov: 31)

Exomes 𝑓: 0.0012 ( 3 hom. )

Consequence

RYR1
NM_000540.3 missense

Scores

Clinical Significance

Likely benign reviewed by expert panel P:1U:15B:6

Conservation

PhyloP100: 2.60

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 Likely_benign. Variant got -4 ACMG points.

BS1

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.4711A>G	p.Ile1571Val	missense_variant	33/106	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.4711A>G	p.Ile1571Val	missense_variant	33/106	5	NM_000540.3	ENSP00000352608	A2	P21817-1
RYR1	ENST00000355481.8 linkuse as main transcript	c.4711A>G	p.Ile1571Val	missense_variant	33/105	1		ENSP00000347667	P4	P21817-2
RYR1	ENST00000599547.6 linkuse as main transcript	c.4711A>G	p.Ile1571Val	missense_variant, NMD_transcript_variant	33/80	2		ENSP00000471601

Frequencies

GnomAD3 genomes

AF:

0.00109

AC:

166

AN:

152128

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000966

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00268

Gnomad ASJ

AF:

0.00144

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.000828

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00162

Gnomad OTH

AF:

0.000955

GnomAD3 exomes

AF:

0.000895

AC:

150

AN:

167524

Hom.:

AF XY:

0.000934

AC XY:

AN XY:

88874

show subpopulations

Gnomad AFR exome

AF:

0.000102

Gnomad AMR exome

AF:

0.00102

Gnomad ASJ exome

AF:

0.000575

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.000668

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00146

Gnomad OTH exome

AF:

0.000642

GnomAD4 exome

AF:

0.00121

AC:

1705

AN:

1408196

Hom.:

Cov.:

AF XY:

0.00125

AC XY:

869

AN XY:

695748

show subpopulations

Gnomad4 AFR exome

AF:

0.0000929

Gnomad4 AMR exome

AF:

0.00102

Gnomad4 ASJ exome

AF:

0.000554

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.000584

Gnomad4 FIN exome

AF:

0.0000207

Gnomad4 NFE exome

AF:

0.00142

Gnomad4 OTH exome

AF:

0.000907

GnomAD4 genome

AF:

0.00109

AC:

166

AN:

152246

Hom.:

Cov.:

AF XY:

0.00109

AC XY:

AN XY:

74440

show subpopulations

Gnomad4 AFR

AF:

0.0000963

Gnomad4 AMR

AF:

0.00268

Gnomad4 ASJ

AF:

0.00144

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.000829

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.00162

Gnomad4 OTH

AF:

0.000945

Alfa

AF:

0.00141

Hom.:

Bravo

AF:

0.00105

ESP6500AA

AF:

0.000229

AC:

ESP6500EA

AF:

0.00129

AC:

ExAC

AF:

0.000603

AC:

Asia WGS

AF:

0.000289

AC:

AN:

3478

ClinVar

Significance: Likely benign

Submissions summary: Pathogenic:1Uncertain:15Benign:6

Revision: reviewed by expert panel

LINK: link

Submissions by phenotype

not provided

Uncertain:6Benign:2

Likely benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Genetic Services Laboratory, University of Chicago	Apr 29, 2014	- -
Uncertain significance, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	May 01, 2024	RYR1: PM3:Strong, PM2, PP3, BS2 -
Uncertain significance, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	Aug 15, 2016	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Revvity Omics, Revvity	Nov 23, 2022	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Feb 15, 2018	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Mayo Clinic Laboratories, Mayo Clinic	Feb 12, 2020	- -
Likely benign, criteria provided, single submitter	clinical testing	GeneDx	Mar 25, 2021	In silico analysis supports that this missense variant does not alter protein structure/function; This variant is associated with the following publications: (PMID: 30611313, 28259615, 28269792, 20681998, 25214167, 25958340, 23919265, 25735680, 24950660, 25960145, 25637381, 24055113, 22473935, 26332594, 31517061) -

Malignant hyperthermia, susceptibility to, 1

Uncertain:1Benign:4

Likely benign, criteria provided, single submitter	clinical testing	Color Diagnostics, LLC DBA Color Health	Mar 01, 2023	- -
Likely benign, no assertion criteria provided	research	CSER _CC_NCGL, University of Washington	Jun 01, 2014	- -
Likely benign, reviewed by expert panel	curation	ClinGen Malignant Hyperthermia Susceptibility Variant Curation Expert Panel, ClinGen	Mar 18, 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 Isoleucine with Valine at codon 1571 of the RYR1 protein, p.(Ile1571Val). The maximum allele frequency for this variant among the six major gnomAD populations is NFE: 0.0014, this is considered to be more common than expected for a pathogenic variant causing autosomal dominantly inherited MHS, BS1. This variant has been reported in five unrelated individuals who have a personal or family history of a malignant hyperthermia reaction, all of these individuals had a positive in vitro contracture test (IVCT) or caffeine halothane contracture test (CHCT) result (if the proband was unavailable for testing, a positive diagnostic test result in a mutation-positive relative was counted), (PMID:25958340, PMID:20681998, PMID:25658027, PMID:25735680). However, the high MAF in the NFE population in gnomAD precludes the use of PS4. No functional studies were identified for this variant. This variant does not reside in a hotspot for pathogenic variants that contribute to MHS. A REVEL score of 0.56 supports neither a pathogenic nor a benign status for this variant. Based on using Bayes to combine criteria this variant is assessed as Likely Benign, (PMID: 29300386). Criteria implemented: BS1. -
Uncertain significance, criteria provided, single submitter	clinical testing	MGZ Medical Genetics Center	Jul 27, 2022	- -
Benign, criteria provided, single submitter	clinical testing	Mendelics	May 28, 2019	- -

Central core myopathy

Pathogenic:1Uncertain:1

Likely pathogenic, criteria provided, single submitter	clinical testing	Laboratory of Medical Genetics, National & Kapodistrian University of Athens	Oct 01, 2021	PM1, PM2, PM3, PP2, PP4, PP5 -
Uncertain significance, no assertion criteria provided	clinical testing	Zotz-Klimas Genetics Lab, MVZ Zotz Klimas	Oct 09, 2023	- -

not specified

Uncertain:2

Uncertain significance, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Apr 25, 2016	Variant identified in a genome or exome case(s) and assessed due to predicted null impact of the variant or pathogenic assertions in the literature or databases. Disclaimer: This variant has not undergone full assessment. The following are preliminary notes: 2 papers describe as LB; ExAC: 0.5% (3/608) Latino chromosomes; ClinVar: 1 LB, 1 VUS; ML: Frequent for disease. 0.2% Eur -
Uncertain significance, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Oct 11, 2023	Variant summary: RYR1 c.4711A>G (p.Ile1571Val) results in a conservative amino acid change in the encoded protein sequence. Three of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 0.0009 in 167524 control chromosomes (gnomAD). c.4711A>G has been reported in the literature in cis with c.10097G>A and c.11798A>G in individuals affected with RYR1-Associated Myopathy (malignant hyperthermia (MH), congenital myopathy, central core disease (CCD), and multi minicore disease (MmD) (examples: Rocha_2014, Savarese_2014, Fiszer_2015, Snoeck_2015, Gillies_2015, Kraeva_2015, Garibaldi_2019, Granger_ 2023). It is unclear if one of the three variants or the combined effect of these mutations are causative for the RYR1-associated diseases in reported individuals. The following publications have been ascertained in the context of this evaluation (PMID: 30611313, 25658027, 25960145, 24950660, 25214167, 25735680, 25958340, 36628841). Fourteen submitters (including ClinGen Malignant Hyperthermia Susceptibility Variant Curation Expert Panel) have cited clinical-significance assessments for this variant to ClinVar after 2014 and classified the variant as VUS (n=9), benign/likely benign (n=4) and likely pathogenic(n=1). Based on the evidence outlined above, the variant was classified as uncertain significance. -

RYR1-related disorder

Uncertain:2

Uncertain significance, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 31, 2024	This sequence change replaces isoleucine, which is neutral and non-polar, with valine, which is neutral and non-polar, at codon 1571 of the RYR1 protein (p.Ile1571Val). This variant is present in population databases (rs146429605, gnomAD 0.1%), and has an allele count higher than expected for a pathogenic variant. Three missense variants, p.Ile1571Val, p.Arg3366His, and p.Tyr3933Cys, which includes this variant (p.Ile1571Val), have been reported together in multiple individuals and families affected with RYR1-related disorders including malignant hyperthermia (MH) syndrome, congenital myopathy, central core disease (CCD), and multi minicore disease (MmD). In some cases, the phase of the three variants along with additional RYR1 variants was established, while in other cases it could not be determined. It is therefore unclear if one of the three variants or the additive effect of some or all of these mutations are causative for the RYR1-associated diseases in reported individuals (PMID: 25958340, 25735680, 25214167, 24950660, 25960145, 25658027, 22473935, 20681998, 28259615, 30611313). ClinVar contains an entry for this variant (Variation ID: 159851). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is not expected to disrupt RYR1 protein function with a negative predictive value of 95%. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. -
Uncertain significance, no assertion criteria provided	clinical testing	Undiagnosed Diseases Network, NIH	Feb 28, 2023	- -

Anterior segment dysgenesis 7

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Molecular Genetics, Royal Melbourne Hospital

Apr 11, 2023

This sequence change in RYR1 is predicted to replace isoleucine with valine at codon 1571, p.(Ile1571Val). The isoleucine residue is moderately conserved (100 vertebrates, UCSC), and is located in exon 33. There is a small physicochemical difference between isoleucine and valine. The highest population minor allele frequency in the population database gnomAD v2.1 is 0.14% (114/83,130 alleles) in the European (non-Finnish) population. This variant is almost always reported in a haplotype with two other RYR1 missense variants, p.[(Ile1571Val);(Arg3366His);(Tyr3933Cys)]. The haplotype has been detected in at least 19 individuals with a phenotype consistent with RYR1-related myopathy with/without malignant hyperthermia susceptibility (MHS). Of those individuals, 14 were compound heterozygous for the variant and a pathogenic or likely pathogenic variant and 8 of those were confirmed in trans by parental/family testing (PMID: 22473935, 23394784, 24950660, 25958340, 25960145, 30611313, 32236737, 35428369). The haplotype segregates with myopathy in a recessive mode of inheritance in at least one family, and there is conflicting evidence for segregation with MHS (PMID: 22473935, 23394784, 25958340). There is limited evidence that the monoallelic haplotype is associated with RYR1-related disease, it has been detected in individuals that unaffected, with MHS, and symptomatic hyperCKaemia (PMID: 25958340, 28259615, 31517061, 32236737). The variant has been detected alone in at least 2 individuals with muscle-related phenotypes, one was compound heterozygous with a pathogenic variant (PMID: 29701772, 35428369). Multiple lines of computational evidence have conflicting predictions for the missense substitution (2/5 algorithms predict deleterious). Based on the classification scheme RMH Modified ACMG Guidelines v1.5.1, this variant is classified as a VARIANT OF UNCERTAIN SIGNIFICANCE. Following criteria are met: PM3_Supporting. The haplotype is classified as LIKELY PATHOGENIC. Following criteria are met: PM3_VeryStrong, PP1. -

See cases

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Laboratorio de Genetica e Diagnostico Molecular, Hospital Israelita Albert Einstein

Jul 11, 2020

ACMG classification criteria: PS4, PM3 -

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

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Fulgent Genetics, Fulgent Genetics

Oct 31, 2018

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.12

BayesDel_addAF

Benign

-0.038

BayesDel_noAF

Pathogenic

0.14

CADD

Benign

DANN

Benign

0.94

DEOGEN2

Benign

0.29

.;T

Eigen

Benign

-0.15

Eigen_PC

Benign

-0.050

FATHMM_MKL

Uncertain

0.93

LIST_S2

Benign

0.74

T;T

M_CAP

Benign

0.080

MetaRNN

Benign

0.016

T;T

MetaSVM

Uncertain

0.18

MutationAssessor

Benign

0.49

N;N

MutationTaster

Benign

0.83

N;N;N

PrimateAI

Benign

0.44

PROVEAN

Benign

0.27

N;N

REVEL

Uncertain

0.56

Sift

Benign

0.73

T;T

Polyphen

0.99

D;B

Vest4

0.65

MVP

0.94

MPC

0.32

ClinPred

0.022

GERP RS

4.0

Varity_R

0.061

gMVP

0.21

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