rs193922839

Variant names:

Your query was ambiguous. Multiple possible variants found:

Variant summary

Our verdict is Likely pathogenic. Variant got 7 ACMG points: 8P and 1B. PS4_ModeratePP3_ModeratePP1_StrongBS2_Supporting

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 arginine with glutamine at codon 3772 of the RYR1 protein, p.(Arg3772Gln). The maximum allele frequency for this variant among the six major gnomAD populations is SAS: 0.000033, a frequency consistent with pathogenicity for MHS. This variant has been reported in eight unrelated individuals who have a personal or family history of a malignant hyperthermia reaction, seven 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), however, three of these individuals were homozygous for this variant and were not considered for PS4, PS4_Moderate was applied (PMID:30236257, 17483490). This variant segregates with MHS in at least seven individuals, PP1_Strong (PMID:19645060, 22473935). This variant has been identified in an individual with a negative IVCT/CHCT result. BS2_Moderate (PMID:30236257). 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 >0.85 (0.888) supports a pathogenic status for this variant, PP3_Moderate. This variant has been classified as Likely Pathogenic. Criteria implemented: PS4_Moderate, PP1_Strong, PP3_Moderate, BS2_Moderate. LINK:https://erepo.genome.network/evrepo/ui/classification/CA023909/MONDO:0007783/012

Frequency

Genomes: 𝑓 0.000013 ( 0 hom., cov: 31)

Exomes 𝑓: 0.0000034 ( 0 hom. )

Consequence

RYR1
NM_000540.3 missense

Scores

Clinical Significance

Likely pathogenic reviewed by expert panel P:10U:2O:1

Conservation

PhyloP100: 10.0

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_pathogenic. Variant got 7 ACMG points.

PS4

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

PP1

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

PP3

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

BS2

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.11315G>A	p.Arg3772Gln	missense_variant	Exon 79 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.11315G>A	p.Arg3772Gln	missense_variant	Exon 79 of 106	5	NM_000540.3	ENSP00000352608.2		P21817-1

Frequencies

GnomAD3 genomes

AF:

0.0000131

AC:

AN:

152108

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000241

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000147

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000160

AC:

AN:

249946

Hom.:

AF XY:

0.00000739

AC XY:

AN XY:

135246

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.0000328

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000177

Gnomad OTH exome

AF:

0.000164

GnomAD4 exome

AF:

0.00000342

AC:

AN:

1461422

Hom.:

Cov.:

AF XY:

0.00000550

AC XY:

AN XY:

726958

show subpopulations

Gnomad4 AFR exome

AF:

0.0000299

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.0000232

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00000180

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

AF:

0.0000131

AC:

AN:

152108

Hom.:

Cov.:

AF XY:

0.0000269

AC XY:

AN XY:

74310

show subpopulations

Gnomad4 AFR

AF:

0.0000241

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000147

Gnomad4 OTH

AF:

0.00

ClinVar

Significance: Likely pathogenic

Submissions summary: Pathogenic:10Uncertain:2Other:1

Revision: reviewed by expert panel

LINK: link

Submissions by phenotype

not provided

Pathogenic:3Uncertain:1Other:1

Nov 22, 2013

PreventionGenetics, part of Exact Sciences

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Dec 16, 2022

Revvity Omics, Revvity

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Jan 06, 2023

GeneDx

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 30236257, 23919265, 19191329, 18253926, 21911697, 21795085, 23553787, 23394784, 27447704, 27377473, 23069638, 31447099, 24091937, 21062345, 30689883, 22473935, 19645060, 17483490, 34106991) -

RYR1 database

Significance: not provided

Review Status: no classification provided

Collection Method: literature only

- -

Oct 22, 2015

Genetic Services Laboratory, University of Chicago

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Malignant hyperthermia, susceptibility to, 1

Pathogenic:3

Nov 28, 2023

All of Us Research Program, National Institutes of Health

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant has been reported in multiple individuals with malignant hyperthermia susceptibility (PMID: 19645060, 30236257, 17483490, 22473935, 23553787, 35849058). This variant is present in 5/281314 total alleles in the Genome Aggregation Database (http://gnomad.broadinstitute.org/). This variant has been reported to co-segregate with disease in seven affected individuals (PMID: 19645060, 22473935). This variant is predicted to be deleterious by in silico analysis. -

Apr 06, 2023

ClinGen Malignant Hyperthermia Susceptibility Variant Curation Expert Panel, ClinGen

Significance: Likely pathogenic

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 arginine with glutamine at codon 3772 of the RYR1 protein, p.(Arg3772Gln). The maximum allele frequency for this variant among the six major gnomAD populations is SAS: 0.000033, a frequency consistent with pathogenicity for MHS. This variant has been reported in eight unrelated individuals who have a personal or family history of a malignant hyperthermia reaction, seven 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), however, three of these individuals were homozygous for this variant and were not considered for PS4, PS4_Moderate was applied (PMID: 30236257, 17483490). This variant segregates with MHS in at least seven individuals, PP1_Strong (PMID:19645060, 22473935). This variant has been identified in an individual with a negative IVCT/CHCT result. BS2_Moderate (PMID: 30236257). 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 >0.85 (0.888) supports a pathogenic status for this variant, PP3_Moderate. This variant has been classified as Likely Pathogenic. Criteria implemented: PS4_Moderate, PP1_Strong, PP3_Moderate, BS2_Moderate. -

Oct 23, 2024

Institute of Human Genetics, University of Leipzig Medical Center

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Criteria applied: PP1_STR,PS4_MOD,PP3_MOD,BS2_MOD -

RYR1-related disorder

Pathogenic:2

Apr 24, 2024

Rady Children's Institute for Genomic Medicine, Rady Children's Hospital San Diego

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.11315G>A (p.Arg3772Gln) variant affects a highly conserved amino acid and is predicted by multiple in silico tools to have a deleterious effect on protein function. This variant has been previously reported as a heterozygous change in individuals with malignant hyperthermia (PMID: 19645060, 30236257) and as a homozygous and compound heterozygous change in individuals with RYR1-related myopathies (PMID: 17483490, 19645060, 23553787, 18253926). A different amino acid change at the same residue (p.Arg3772Gln) have been previously reported in individuals with malignant hyperthermia and RYR1-related myopathy (PMID: 19191329, 21795085, 23919265, 24091937, 30611313). It is present in the heterozygous state in the gnomAD v4 population database at a frequency of 0.0004% (7/1613530) and thus is presumed to be rare. Based on the available evidence, the c.11315G>A (p.Arg3772Gln) variant is classified as Pathogenic. -

Aug 31, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change replaces arginine, which is basic and polar, with glutamine, which is neutral and polar, at codon 3772 of the RYR1 protein (p.Arg3772Gln). This variant is present in population databases (rs193922839, gnomAD 0.003%). This missense change has been observed in individuals with autosomal recessive RYR1-related myopathy and malignant hyperthermia susceptibility (PMID: 17483490, 19645060). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 133012). Invitae Evidence Modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) indicates that this missense variant is expected to disrupt RYR1 protein function with a positive predictive value of 95%. This variant disrupts the p.Arg3772 amino acid residue in RYR1. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 19191329, 21062345, 23919265, 24091937). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. For these reasons, this variant has been classified as Pathogenic. -

Inborn genetic diseases

Pathogenic:1

May 05, 2023

Ambry Genetics

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.11315G>A (p.R3772Q) alteration is located in exon 79 (coding exon 79) of the RYR1 gene. This alteration results from a G to A substitution at nucleotide position 11315, causing the arginine (R) at amino acid position 3772 to be replaced by a glutamine (Q)._x000D_ _x000D_ Based on the available evidence, the RYR1 c.11315G>A (p.R3772Q) alteration is classified as likely pathogenic for autosomal dominant malignant hyperthermia susceptibility (MHS) and autosomal recessive RYR1-related myopathy; however, its clinical significance for autosomal dominant RYR1-related myopathy is unclear. Based on data from gnomAD, the A allele has an overall frequency of 0.002% (5/281314) total alleles studied. This variant has been reported in multiple unrelated individuals who had a positive in vitro contracture test (IVCT) or caffeine halothane contracture test (CHCT), or who have a personal or family history of a malignant hyperthermia reaction (Zhou, 2007; Carpenter, 2009; Klein, 2012; Miller, 2018). In addition, this alteration has been observed in the homozygous or compound heterozygous state in multiple individuals with myopathy (Zhou, 2007; Monnier, 2008; Carpenter, 2009; Klein, 2012; Hwang, 2012; Maggi, 2013; Stehlíková, 2017; Miller, 2018; Babi Boovi, 2021). This variant has been observed to segregate with autosomal dominant malignant hyperthermia susceptibility (MHS) and/or autosomal recessive myopathy in multiple families (Carpenter, 2009; Klein, 2012). This amino acid position is highly conserved in available vertebrate species. The in silico prediction for this alteration is inconclusive. Based on the available evidence, this alteration is classified as likely pathogenic. -

Malignant hyperthermia of anesthesia;C0027868:Neuromuscular disease

Pathogenic:1

Nov 01, 2017

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The p.Arg3772Gln variant in RYR1 has been reported in the heterozygous state in 1 individual with a malignant hyperthermia susceptibility (MHS) phenotype (Carpe nter 2009) and in the homozygous or compound heterozygous state in at least 10 i ndividuals with congenital myopathy (Zhou 2007, Monnier 2008, Carpenter 2009, Kl ein 2012). Three of the individuals with congenital myopathy also have a MHS phe notype (Zhou 2007, Carpenter 2009, Klein 2012). This variant segregated with mal ignant hyperthermia in 9 affected relatives (8 heterozygotes and 1 homozygote) f rom 3 families (Carpenter 2009, Klein 2012) and with congenital myopathy in the homozygous or compound heterozygous state in 6 affected relatives from 3 familie s, 3 of whom who also had MH (Zhou 2007, Carpenter 2009, Klein 2012). mRNA expr ession studies from muscle biopsies of patients homozygous for the p.Arg3772Gln variant provide some evidence that it causes decreased mRNA expression (Zhou et al. 2013. This variant has been reported by other clinical laboratories in ClinV ar (Variation ID 133012) and has been identified in 2/11052 European chromosomes by the genome Aggregation Database (gnomAD, http://gnomad.broadinstitute.org; d bSNP rs193922839). In summary, the p.Arg3772Gln variant meets criteria to be cla ssified as pathogenic for malignant hyperthermia in an autosomal dominant manner and congenital myopathy in an autosomal recessive manner based upon presence in multiple affected individuals, segregation studies, very low frequency in the g eneral population and functional studies. -

Scoliosis;C0221629:Proximal muscle weakness;C0427064:Pelvic girdle muscle weakness;C1836609:Progressive distal muscle weakness;C1837658:Delayed gross motor development

Uncertain:1

Aug 29, 2014

Centre for Mendelian Genomics, University Medical Centre Ljubljana

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.86

BayesDel_addAF

Pathogenic

0.26

BayesDel_noAF

Pathogenic

0.24

CADD

Uncertain

DANN

Uncertain

0.99

DEOGEN2

Uncertain

0.74

.;D;.;.

Eigen

Pathogenic

0.89

Eigen_PC

Pathogenic

0.82

FATHMM_MKL

Pathogenic

0.98

LIST_S2

Pathogenic

1.0

D;D;D;D

M_CAP

Pathogenic

0.66

MetaRNN

Pathogenic

0.93

D;D;D;D

MetaSVM

Pathogenic

0.96

MutationAssessor

Uncertain

2.5

.;M;.;.

PrimateAI

Uncertain

0.68

PROVEAN

Uncertain

-3.4

D;D;.;.

REVEL

Pathogenic

0.89

Sift

Pathogenic

0.0

D;D;.;.

Sift4G

Pathogenic

0.0

.;.;D;D

Polyphen

1.0

D;D;.;.

Vest4

0.62

MutPred

0.77

.;Loss of MoRF binding (P = 0.0177);.;.;

MVP

1.0

MPC

0.69

ClinPred

0.95

GERP RS

4.8

Varity_R

0.66

gMVP

0.36

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