19-38500655-G-A

Position:

• chr19-38500655-G-A

Variant summary

Our verdict is Pathogenic. Variant got 14 ACMG points: 14P and 0B. PS4 PP1_Strong PP3_Moderate PM1 PS3_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 2458 of the RYR1 protein, p.(Arg2458His). The maximum allele frequency for this variant among the six major gnomAD populations is EAS: 0.000054, a frequency consistent with pathogenicity for MHS. This variant has been reported in 26 unrelated individuals who have a personal or family history of a malignant hyperthermia reaction, 23 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), PS4 (PMID:30236257, 16163667, 22415532, 9450902, 16732084, 21157159 and others). This variant segregates with MHS in 10 individuals, PP1_Strong (PMID:30236257). Functional studies in HEK293 cells and dyspedic myotubes show an increased sensitivity to RYR1 agonists, PS3_Moderate (PMID:27586648, 12732639). 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 >0.85 (0.959) supports a pathogenic status for this variant, PP3_Moderate. This variant has been classified as Pathogenic. Criteria implemented: PS3_Moderate, PS4, PM1, PP1_Strong, PP3_Moderate. LINK:https://erepo.genome.network/evrepo/ui/classification/CA024787/MONDO:0007783/012

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000055 (0 hom.)
• Consequence: RYR1 NM_000540.3 missense
• Clinical Significance: drug response reviewed by expert panel P:7 O:9
• Conservation: PhyloP100: 9.99

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]

ACMG classification

Verdict is Pathogenic. Variant got 14 ACMG points.

• PS3: For more information check the summary or visit ClinGen Evidence Repository.
• PS4: For more information check the summary or visit ClinGen Evidence Repository.
• PM1: 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.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
RYR1	NM_000540.3	c.7373G>A	p.Arg2458His	missense_variant	46/106	ENST00000359596.8	NP_000531.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
RYR1	ENST00000359596.8	c.7373G>A	p.Arg2458His	missense_variant	46/106	5	NM_000540.3	ENSP00000352608	A2
RYR1	ENST00000355481.8	c.7373G>A	p.Arg2458His	missense_variant	46/105	1		ENSP00000347667	P4
RYR1	ENST00000594335.5	c.827G>A	p.Arg276His	missense_variant, NMD_transcript_variant	7/49	1		ENSP00000470927
RYR1	ENST00000599547.6	c.7373G>A	p.Arg2458His	missense_variant, NMD_transcript_variant	46/80	2		ENSP00000471601

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD3 exomes AF: 0.00000796 AC: 2 AN: 251238 Hom.: 0 AF XY: 0.00000736 AC XY: 1 AN XY: 135880

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.0000544

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00000880

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000547 AC: 8 AN: 1461666 Hom.: 0 Cov.: 31 AF XY: 0.00000963 AC XY: 7 AN XY: 727118

Gnomad4 AFR exome AF: 0.00

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: 0.00000719

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

Alfa AF: 0.0000492 Hom.: 0

ExAC AF: 0.0000165 AC: 2

ClinVar

Significance: drug response

Submissions summary: Pathogenic:7 Other:9

Revision: reviewed by expert panel

Submissions by phenotype

Malignant hyperthermia, susceptibility to, 1 Pathogenic:2 Other:1

Likely pathogenic, criteria provided, single submitter	clinical testing	Human Genome Sequencing Center Clinical Lab, Baylor College of Medicine	Oct 08, 2018	The c.7373G>A(p.Arg2458His) variant in the RYR1 gene has been reported in multiple unrelated patients with malignant hyperthermia and segregates with disease in two unrelated families (PMID: 9450902, 22415532, 19648156). In silico analyses of this conserved variant predict damaging consequences on the RYR1 protein. The functional study also demonstrated that the variant increased the Ca2+-induced Ca2+release (CICR) activity and had enhanced sensitivity to caffeine and halothane(PMID: 12732639, 22415532, 27586648). Therefore, this c.7373G>A(p.Arg2458His) variant is classified as likely pathogenic for malignant hyperthermia. -
risk factor, no assertion criteria provided	literature only	OMIM	Jan 01, 1998	- -
Likely pathogenic, criteria provided, single submitter	clinical testing	All of Us Research Program, National Institutes of Health	Jun 26, 2023	This missense variant replaces arginine with histidine at codon 2458 of the RYR1 protein. Computational prediction suggests that this variant may have deleterious impact on protein structure and function (internally defined REVEL score threshold >= 0.7, PMID: 27666373). Functional studies in myotubes and HEK293 cells have shown this variant causes increased sensitivity to caffeine and/or 4-CmC in comparison to wild-type RYR1 (PMID: 12732639, 27586648). This variant has been reported in at least 20 families and individuals affected with malignant hyperthermia susceptibility (PMID: 14985404, 16732084, 18564801, 19648156, 22415532, 30236257, 9450902). This variant has been identified in 2/251238 chromosomes in the general population by the Genome Aggregation Database (gnomAD). Based on the available evidence, this variant is classified as Likely Pathogenic. -

not provided Pathogenic:2 Other:1

not provided, no classification provided	literature only	Leiden Muscular Dystrophy (RYR1)	-	- -
Likely pathogenic, criteria provided, single submitter	clinical testing	Clinical Genetics and Genomics, Karolinska University Hospital	Feb 21, 2017	- -
Pathogenic, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Oct 18, 2013	- -

RYR1-related disorder Pathogenic:2

Pathogenic, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 24, 2024	This sequence change replaces arginine, which is basic and polar, with histidine, which is basic and polar, at codon 2458 of the RYR1 protein (p.Arg2458His). This variant is present in population databases (rs121918594, gnomAD 0.006%). This missense change has been observed in individuals with autosomal dominant malignant hyperthermia (PMID: 9450902, 12700608, 16732084, 18564801, 19648156, 22415532, 30236257). It has also been observed to segregate with disease in related individuals. This variant has been reported in individual(s) with autosomal recessive arthrogyrposis multiplex congenita (PMID: 24319099); however, the role of the variant in this condition is currently unclear. ClinVar contains an entry for this variant (Variation ID: 12972). 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 expected to disrupt RYR1 protein function with a positive predictive value of 95%. Experimental studies have shown that this missense change affects RYR1 function (PMID: 9334205, 9873004, 12732639, 27586648). For these reasons, this variant has been classified as Pathogenic. -
Pathogenic, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	Jan 05, 2023	The RYR1 c.7373G>A variant is predicted to result in the amino acid substitution p.Arg2458His. This variant has been reported in over 25 individuals and 9 families with malignant hyperthermia (MH) (Manning et al 1998. PubMed ID: 9450902; Carpenter D et al 2009. PubMed ID: 19648156; Li DW et al 2017. PubMed ID: 29355282; Miller DM et al 2018. PubMed ID: 30236257; Yeh HM et al 2020. PubMed ID: 32919876; Fusto et al. 2022. PubMed ID: 35428369). This variant is listed by the European Malignant Hyperthermia group as a clear diagnostic variant for MH (https://www.emhg.org/diagnostic-mutations). Functional studies indicate the p.Arg2458His variant results in enhanced sensitivity to caffeine and halothane (Tong et al. 1999. PubMed ID: 9873004; Murayama et al. 2016. PubMed ID: 27586648; Yang et al. 2003. PubMed ID: 12732639). The c.7373G>A variant has also been reported in the compound heterozygous state with another RYR1 variant in at least two individuals with arthrogryposis multiplex congenita, indicating this variant is also causative for autosomal recessive RYR1-related disorders (Laquérriere A et al 2013. PubMed ID: 24319099) This variant is reported in 0.0054% of alleles in individuals of East Asian descent in gnomAD (http://gnomad.broadinstitute.org/variant/19-38991295-G-A). This variant is interpreted as pathogenic. THIS PATIENT IS SUSCEPTIBLE TO MALIGNANT HYPERTHERMIA! Alternative anesthetics should be used. The patient should consider wearing an ID bracelet or other alert device (see www.mhaus.org). -

Malignant hyperthermia of anesthesia Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Jun 11, 2020

The p.Arg2458His variant in RYR1 has been reported in >15 individuals with malignant hyperthermia and segregated in >10 affected family members (Li 2017, Shepherd 2006, Ibarra 2006, Carpenter 2009, Laquerriere 2014, Gillies 2008, Manning 1998, Rubegni 2019, Robinson 2006, Miller 2018, Kaufmann 2012). This variant has been identified in 1/18382 East Asian chromosomes by gnomAD (http://gnomad.broadinstitute.org) and in ClinVar by the PharmGKB expert panel with evidence level 1A for susceptibility to malignant hyperthermia, the annotation for a variant-drug combination in a CPIC or medical society-endorsed PGx guideline (Variation ID 12972). Computational prediction tools and conservation analysis suggest that this variant may impact the protein. Furthermore, in vitro functional studies indicated that this variant confers increase sensitivity to RYR1-agonists such as caffeine (Yang 2003, Tong 1997, Tong 1999). In summary, this variant meets criteria to be classified as pathogenic for autosomal dominant malignant hyperthermia. ACMG/AMP Criteria applied: PS4, PP1_Strong, PM2, PP3, PS3_Supporting. -

methoxyflurane response - Toxicity Other:1

drug response, reviewed by expert panel

curation

PharmGKB

Mar 24, 2021

PharmGKB Level of Evidence 1A: Level 1A clinical annotations describe variant-drug combinations that have variant-specific prescribing guidance available in a current clinical guideline annotation or an FDA-approved drug label annotation. Annotations of drug labels or clinical guidelines must give prescribing guidance for specific variants (e.g. CYP2C9*3, HLA-B*57:01) or provide mapping from defined allele functions to diplotypes and phenotypes to be used as supporting evidence for a level 1A clinical annotation. Level 1A clinical annotations must also be supported by at least one publication in addition to a clinical guideline or drug label with variant-specific prescribing guidance. Drug-variant association: Toxicity

sevoflurane response - Toxicity Other:1

drug response, reviewed by expert panel

curation

PharmGKB

Mar 24, 2021

PharmGKB Level of Evidence 1A: Level 1A clinical annotations describe variant-drug combinations that have variant-specific prescribing guidance available in a current clinical guideline annotation or an FDA-approved drug label annotation. Annotations of drug labels or clinical guidelines must give prescribing guidance for specific variants (e.g. CYP2C9*3, HLA-B*57:01) or provide mapping from defined allele functions to diplotypes and phenotypes to be used as supporting evidence for a level 1A clinical annotation. Level 1A clinical annotations must also be supported by at least one publication in addition to a clinical guideline or drug label with variant-specific prescribing guidance. Drug-variant association: Toxicity

isoflurane response - Toxicity Other:1

drug response, reviewed by expert panel

curation

PharmGKB

Mar 24, 2021

PharmGKB Level of Evidence 1A: Level 1A clinical annotations describe variant-drug combinations that have variant-specific prescribing guidance available in a current clinical guideline annotation or an FDA-approved drug label annotation. Annotations of drug labels or clinical guidelines must give prescribing guidance for specific variants (e.g. CYP2C9*3, HLA-B*57:01) or provide mapping from defined allele functions to diplotypes and phenotypes to be used as supporting evidence for a level 1A clinical annotation. Level 1A clinical annotations must also be supported by at least one publication in addition to a clinical guideline or drug label with variant-specific prescribing guidance. Drug-variant association: Toxicity

enflurane response - Toxicity Other:1

drug response, reviewed by expert panel

curation

PharmGKB

Mar 24, 2021

PharmGKB Level of Evidence 1A: Level 1A clinical annotations describe variant-drug combinations that have variant-specific prescribing guidance available in a current clinical guideline annotation or an FDA-approved drug label annotation. Annotations of drug labels or clinical guidelines must give prescribing guidance for specific variants (e.g. CYP2C9*3, HLA-B*57:01) or provide mapping from defined allele functions to diplotypes and phenotypes to be used as supporting evidence for a level 1A clinical annotation. Level 1A clinical annotations must also be supported by at least one publication in addition to a clinical guideline or drug label with variant-specific prescribing guidance. Drug-variant association: Toxicity

halothane response - Toxicity Other:1

drug response, reviewed by expert panel

curation

PharmGKB

Mar 24, 2021

PharmGKB Level of Evidence 1A: Level 1A clinical annotations describe variant-drug combinations that have variant-specific prescribing guidance available in a current clinical guideline annotation or an FDA-approved drug label annotation. Annotations of drug labels or clinical guidelines must give prescribing guidance for specific variants (e.g. CYP2C9*3, HLA-B*57:01) or provide mapping from defined allele functions to diplotypes and phenotypes to be used as supporting evidence for a level 1A clinical annotation. Level 1A clinical annotations must also be supported by at least one publication in addition to a clinical guideline or drug label with variant-specific prescribing guidance. Drug-variant association: Toxicity

desflurane response - Toxicity Other:1

drug response, reviewed by expert panel

curation

PharmGKB

Mar 24, 2021

PharmGKB Level of Evidence 1A: Level 1A clinical annotations describe variant-drug combinations that have variant-specific prescribing guidance available in a current clinical guideline annotation or an FDA-approved drug label annotation. Annotations of drug labels or clinical guidelines must give prescribing guidance for specific variants (e.g. CYP2C9*3, HLA-B*57:01) or provide mapping from defined allele functions to diplotypes and phenotypes to be used as supporting evidence for a level 1A clinical annotation. Level 1A clinical annotations must also be supported by at least one publication in addition to a clinical guideline or drug label with variant-specific prescribing guidance. Drug-variant association: Toxicity

succinylcholine response - Toxicity Other:1

drug response, reviewed by expert panel

curation

PharmGKB

Mar 24, 2021

PharmGKB Level of Evidence 1A: Level 1A clinical annotations describe variant-drug combinations that have variant-specific prescribing guidance available in a current clinical guideline annotation or an FDA-approved drug label annotation. Annotations of drug labels or clinical guidelines must give prescribing guidance for specific variants (e.g. CYP2C9*3, HLA-B*57:01) or provide mapping from defined allele functions to diplotypes and phenotypes to be used as supporting evidence for a level 1A clinical annotation. Level 1A clinical annotations must also be supported by at least one publication in addition to a clinical guideline or drug label with variant-specific prescribing guidance. Drug-variant association: Toxicity

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.52
BayesDel_addAF	Pathogenic	0.43	D
BayesDel_noAF	Pathogenic	0.55
CADD	Pathogenic	28
DANN	Uncertain	1.0
DEOGEN2	Pathogenic	0.86	.;D
Eigen	Pathogenic	0.79
Eigen_PC	Pathogenic	0.71
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Pathogenic	1.0	D;D
M_CAP	Pathogenic	0.68	D
MetaRNN	Pathogenic	0.97	D;D
MetaSVM	Pathogenic	1.1	D
MutationAssessor	Uncertain	2.6	M;M
MutationTaster	Benign	1.0	D;D;D
PrimateAI	Pathogenic	0.83	D
PROVEAN	Pathogenic	-4.6	D;D
REVEL	Pathogenic	0.96
Sift	Uncertain	0.0010	D;D
Polyphen		1.0	D;D
Vest4		0.75
MutPred		0.88		Gain of catalytic residue at L2460 (P = 0.0441);Gain of catalytic residue at L2460 (P = 0.0441);
MVP		1.0
MPC		0.38
ClinPred		0.98	D
GERP RS		4.0
Varity_R		0.67
gMVP		0.86

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

Other links and lift over

dbSNP: rs121918594; hg19: chr19-38991295; COSMIC: COSV62093719;