rs144336148

Positions:

chr19-38455472-G-A

Variant summary

Our verdict is Uncertain significance. Variant got 4 ACMG points: 4P and 0B. PM1PS3_Moderate

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 Histidine at codon 533 of the RYR1 protein, p.(Arg533His). The maximum allele frequency for this variant among the six major gnomAD populations is AFR: 0.00044, a frequency consistent with pathogenicity for MHS. This variant has been reported in 3 unrelated individuals who have a personal or family history of a malignant hyperthermia reaction, 2 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:30236257, PMID:16732084). However, the high MAF in the AFR population in gnomAD precludes the use of PS4. Functional studies in HEK293 cells show an increased sensitivity to RYR1 agonists, PS3_Moderate, (PMID:23459219). This variant resides in a region of RYR1 considered to be a hotspot for pathogenic variants that contribute to MHS, PM1 (PMID:21118704). A REVEL score of 0.824 supports neither a pathogenic nor a benign status for this variant. This variant has been classified as a Variant of Unknown Significance. Criteria implemented: PS3_Moderate, PM1. LINK:https://erepo.genome.network/evrepo/ui/classification/CA024295/MONDO:0007783/012

Frequency

Genomes: 𝑓 0.00026 ( 0 hom., cov: 31)

Exomes 𝑓: 0.00011 ( 0 hom. )

Consequence

RYR1
NM_000540.3 missense

Scores

Clinical Significance

Uncertain significance reviewed by expert panel P:7U:9O:1

Conservation

PhyloP100: 8.17

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 Uncertain_significance. Variant got 4 ACMG points.

PS3

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

PM1

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 link	c.1598G>A	p.Arg533His	missense_variant	15/106	ENST00000359596.8	NP_000531.2	P21817-1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	UniProt
RYR1	ENST00000359596.8 link	c.1598G>A	p.Arg533His	missense_variant	15/106	5	NM_000540.3	ENSP00000352608.2	P21817-1
RYR1	ENST00000355481.8 link	c.1598G>A	p.Arg533His	missense_variant	15/105	1		ENSP00000347667.3	P21817-2
RYR1	ENST00000599547.6 link	n.1598G>A		non_coding_transcript_exon_variant	15/80	2		ENSP00000471601.2	M0R127

Frequencies

GnomAD3 genomes

AF:

0.000256

AC:

AN:

152108

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000628

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:

0.000176

Gnomad OTH

AF:

0.000478

GnomAD3 exomes

AF:

0.000107

AC:

AN:

251492

Hom.:

AF XY:

0.0000883

AC XY:

AN XY:

135920

show subpopulations

Gnomad AFR exome

AF:

0.000492

Gnomad AMR exome

AF:

0.000145

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.000123

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.000115

AC:

168

AN:

1461890

Hom.:

Cov.:

AF XY:

0.000121

AC XY:

AN XY:

727246

show subpopulations

Gnomad4 AFR exome

AF:

0.000717

Gnomad4 AMR exome

AF:

0.0000894

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.0000252

Gnomad4 SAS exome

AF:

0.0000116

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.000117

Gnomad4 OTH exome

AF:

0.000132

GnomAD4 genome

AF:

0.000256

AC:

AN:

152108

Hom.:

Cov.:

AF XY:

0.000229

AC XY:

AN XY:

74288

show subpopulations

Gnomad4 AFR

AF:

0.000628

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:

0.000176

Gnomad4 OTH

AF:

0.000478

Alfa

AF:

0.000175

Hom.:

Bravo

AF:

0.000306

ESP6500AA

AF:

0.000908

AC:

ESP6500EA

AF:

0.000349

AC:

ExAC

AF:

0.0000988

AC:

EpiCase

AF:

0.000164

EpiControl

AF:

0.000178

ClinVar

Significance: Uncertain significance

Submissions summary: Pathogenic:7Uncertain:9Other:1

Revision: reviewed by expert panel

LINK: link

Submissions by phenotype

not provided

Pathogenic:3Uncertain:2Other:1

Likely pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Oct 31, 2024	Published functional studies demonstrate a damaging effect with increased sensitivity to a RYR1 agonist compared to wild-type controls (PMID: 23459219); 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: 10484775, 24055113, 25637381, 27147545, 30236257, 11668625, 31301762, 33767344, 32381029, 32919876, Kanzaki2022[Paper], 35718563, 34890165, 16732084, 23459219, 30499100, 16084090, 16917943) -
not provided, no classification provided	literature only	Leiden Muscular Dystrophy (RYR1)	-	- -
Likely pathogenic, criteria provided, single submitter	clinical testing	AiLife Diagnostics, AiLife Diagnostics	Dec 16, 2021	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Jun 06, 2016	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Revvity Omics, Revvity	Aug 30, 2023	- -
Likely pathogenic, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Aug 01, 2024	RYR1: PM1, PM5, PS4:Moderate, PS3:Supporting -

Malignant hyperthermia, susceptibility to, 1

Pathogenic:2Uncertain:4

Likely pathogenic, criteria provided, single submitter	clinical testing	MGZ Medical Genetics Center	Jun 15, 2022	- -
Uncertain significance, criteria provided, single submitter	clinical testing	All of Us Research Program, National Institutes of Health	Jul 20, 2024	This missense variant replaces arginine with histidine at codon 533 of the RYR1 protein. Computational prediction suggests that this variant may have deleterious impact on protein structure and function. A functional study has shown cells expressing this variant have increased sensitivity to RYR1 agonists compared to cells expressing wild-type RYR1 (PMID: 23459219). A different variant occurring at the same codon, c.1597C>T (p.Arg533Cys), is a well-documented pathogenic variant (ClinVar Variation ID: 133102), indicating that Arg at this position may be important for RYR1 protein function. This p.Arg533His variant has been reported in at least two families affected with malignant hyperthermia susceptibility (PMID: 30236257). This variant occurs at an elevated frequency in the general population and has been identified in 32/282858 chromosomes in the general population by the Genome Aggregation Database (gnomAD). The available evidence is insufficient to determine the role of this variant in disease conclusively. Therefore, this variant is classified as a Variant of Uncertain Significance. -
Uncertain significance, no assertion criteria provided	research	CSER _CC_NCGL, University of Washington	Jun 01, 2014	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Molecular Genetics, Royal Melbourne Hospital	Mar 30, 2023	This sequence change is predicted to replace arginine with histidine at codon 533 of the RYR1 protein (p.(Arg533His)). The arginine residue is very highly conserved (100 vertebrates, UCSC), and located in the IP3 receptor type 1 binding core, domain 2. There is a small physicochemical difference between arginine and histidine. The variant is present in a large population cohort at a frequency of 0.03% (rs144336148, gnomAD v3.1). The variant has been reported in two affected individuals with malignant hyperthermia susceptibility in heterozygous form (PMID: 30236257) and in homozygous form in an individual who was also homozygous for another RYR1 variant (PMID: 16732084). Experimental studies in HEK-293 cells have demonstrated that this missense variant affects calcium channel function in vitro (PMID: 23459219). This missense variant is associated with a positive in vitro contracture test for malignant hyperthermia susceptibility (Royal Melbourne Hospital). Multiple lines of computational evidence have conflicting predictions for the missense substitution (3/6 algorithms predict deleterious). A missense variant at the same codon with a large physicochemical difference, p.(Arg533Cys), is listed as a diagnostic mutation by the European Malignant Hyperthermia Group. The p.(Arg533His) missense variant is listed as a diagnostic mutation by the European Malignant Hyperthermia Group, but as a variant of uncertain significance by ClinGen. Based on the classification guideline RMH Modified ACMG Guidelines v1.3.1, this variant is classified as a VARIANT OF UNCERTAIN SIGNIFICANCE. The following criteria are met: PS3, PP4. -
Uncertain significance, reviewed by expert panel	curation	ClinGen Malignant Hyperthermia Susceptibility Variant Curation Expert Panel, ClinGen	Apr 10, 2023	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 Histidine at codon 533 of the RYR1 protein, p.(Arg533His). The maximum allele frequency for this variant among the six major gnomAD populations is AFR: 0.00044, a frequency consistent with pathogenicity for MHS. This variant has been reported in 3 unrelated individuals who have a personal or family history of a malignant hyperthermia reaction, 2 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:30236257, PMID:16732084). However, the high MAF in the AFR population in gnomAD precludes the use of PS4. Functional studies in HEK293 cells show an increased sensitivity to RYR1 agonists, PS3_Moderate, (PMID:23459219). This variant resides in a region of RYR1 considered to be a hotspot for pathogenic variants that contribute to MHS, PM1 (PMID: 21118704). A REVEL score of 0.824 supports neither a pathogenic nor a benign status for this variant. This variant has been classified as a Variant of Unknown Significance. Criteria implemented: PS3_Moderate, PM1. -
Likely pathogenic, criteria provided, single submitter	clinical testing	Institute of Human Genetics, University of Leipzig Medical Center	Jul 05, 2024	Criteria applied: PS4_MOD,PS3_MOD,PM5,PM1_SUP,PP3 -

RYR1-related disorder

Uncertain:2

Uncertain significance, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	May 23, 2023	The RYR1 c.1598G>A variant is predicted to result in the amino acid substitution p.Arg533His. This variant has been reported in several individuals who have had malignant hyperthermia (MH) events or are MH-susceptible via the in vitro muscle contracture test (Brandt et al. 1999. PubMed ID: 10484775; Robinson et al. 2006. PubMed ID: 16917943; Ibarra et al. 2006. PubMed ID: 16732084; Miller et al. 2018. PubMed ID: 30236257). A different substitution at the same amino acid (p.Arg533Cys) was reported to segregate with in vitro contracture test results in a large three generation family (Tammaro et al. 2003. PubMed ID: 12709367). The c.1598G>A (p.Arg533His) variant was reported to affect Ca++ channel function in an in vitro assay (Sato et al. 2013. PubMed ID: 23459219). Exon 15 is a hotspot in the RYR1 gene for pathogenic MH variants. However, the c.1598G>A (p.Arg533His) variant is reported in 0.04% of alleles in individuals of African descent in gnomAD (http://gnomad.broadinstitute.org/variant/19-38946112-G-A) and at PreventionGenetics we have observed this variant in many individuals with no indication of MH related events (internal data). An expert ClinGen panel interprets the c.1598G>A variant as uncertain (https://www.ncbi.nlm.nih.gov/clinvar/variation/133103/). Although we suspect this variant could contribute to MHS, at this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence. -
Uncertain significance, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Nov 01, 2022	This sequence change replaces arginine, which is basic and polar, with histidine, which is basic and polar, at codon 533 of the RYR1 protein (p.Arg533His). This variant is present in population databases (rs144336148, gnomAD 0.06%). This missense change has been observed in individual(s) with clinical features of RYR1-related conditions (PMID: 10484775). ClinVar contains an entry for this variant (Variation ID: 133103). 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) has been performed at Invitae for this missense variant, however the output from this modeling did not meet the statistical confidence thresholds required to predict the impact of this variant on RYR1 protein function. Experimental studies have shown that this missense change affects RYR1 function (PMID: 23459219). 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. -

Malignant hyperthermia of anesthesia

Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Nov 19, 2024

Variant summary: RYR1 c.1598G>A (p.Arg533His) results in a non-conservative amino acid change located in the RIH domain (IPR000699) of the encoded protein sequence. Four of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 0.00011 in 251492 control chromosomes, predominantly at a frequency of 0.00049 within the African or African-American subpopulation in the gnomAD database. c.1598G>A has been reported in the literature in individuals affected with autosomal dominant Malignant Hyperthermia Susceptibility. In families with this variant, 5 transmissions of the variant allele and 1 transmission of the reference allele to affected individuals were reported (example, Miller_2018, Ibarra_2006, Klincova_2022). These data indicate that the variant may be associated with disease. A different variant affecting the same codon has been classified as pathogenic by our lab (c.1597C>T, p.Arg533Cys), supporting the critical relevance of codon 533 to RYR1 protein function. At least one publication reports experimental evidence evaluating an impact on protein function. The most pronounced variant effect results in >20-fold increased sensitivity to a ryanodine receptor agonist in vitro (example, Sato_2013). The following publications have been ascertained in the context of this evaluation (PMID: 30236257, 16732084, 23459219, 35718563). ClinVar contains an entry for this variant (Variation ID: 133103). Based on the evidence outlined above, the variant was classified as likely pathogenic. -

Central core myopathy

Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

Molecular Diagnostics Laboratory, M Health Fairview: University of Minnesota

Jul 12, 2019

- -

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

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Fulgent Genetics, Fulgent Genetics

Mar 28, 2022

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Uncertain

0.52

BayesDel_addAF

Pathogenic

0.18

BayesDel_noAF

Pathogenic

0.38

CADD

Pathogenic

DANN

Uncertain

1.0

DEOGEN2

Pathogenic

0.82

.;D

Eigen

Uncertain

0.49

Eigen_PC

Uncertain

0.47

FATHMM_MKL

Pathogenic

1.0

LIST_S2

Pathogenic

0.99

D;D

M_CAP

Uncertain

0.21

MetaRNN

Uncertain

0.72

D;D

MetaSVM

Pathogenic

0.81

MutationAssessor

Benign

1.6

L;L

PrimateAI

Uncertain

0.64

PROVEAN

Uncertain

-3.4

D;D

REVEL

Pathogenic

0.82

Sift

Benign

0.63

T;T

Polyphen

1.0

D;D

Vest4

0.68

MVP

0.99

MPC

1.1

ClinPred

0.13

GERP RS

4.0

Varity_R

0.29

gMVP

0.83

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.010

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