19-38499997-G-T

Variant names:

• chr19-38499997-G-T
• rs28933396
• NM_000540.3:c.7304G>T

Variant summary

Our verdict is Likely pathogenic. Variant got 7 ACMG points: 7P and 0B. PM5 PS4_Moderate PM1_Supporting PP3_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 leucine at codon 2435 of the RYR1 protein, p.(Arg2435Leu). This variant was not present in a large population database (gnomAD) at the time this variant was interpreted. This variant has been reported in four unrelated individuals who have a personal or family history of a malignant hyperthermia reaction, three 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_Moderate (PMID:10051009, PMID:23558838, PMID:30236257, The UK (Leeds) MH Unit). No functional studies were identified for this variant. This variant resides in a region of RYR1 considered to be a hotspot for pathogenic variants that contribute to MHS, use PM1_Supporting to avoid overweighting with PM5 (PMID:21118704). Another variant has been assessed as pathogenic occurs at this codon, p.(Arg2435His), PM5. A REVEL score >0.85 (0.948) supports a pathogenic status for this variant, PP3_Moderate. This variant has been classified as Likely Pathogenic. Criteria implemented: PS4_Moderate, PM1_Supporting, PM5, PP3_Moderate. LINK:https://erepo.genome.network/evrepo/ui/classification/CA024753/MONDO:0007783/012

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000027 (0 hom.)
• Consequence: RYR1 NM_000540.3 missense
• Clinical Significance: Likely pathogenic reviewed by expert panel P:4 O:1
• Conservation: PhyloP100: 9.98

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 Likely_pathogenic. Variant got 7 ACMG points.

• PS4: For more information check the summary or visit ClinGen Evidence Repository.
• PM1: For more information check the summary or visit ClinGen Evidence Repository.
• PM5: 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 rank	MANE	Protein	UniProt
RYR1	NM_000540.3	c.7304G>T	p.Arg2435Leu	missense_variant	Exon 45 of 106	ENST00000359596.8	NP_000531.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
RYR1	ENST00000359596.8	c.7304G>T	p.Arg2435Leu	missense_variant	Exon 45 of 106	5	NM_000540.3	ENSP00000352608.2
RYR1	ENST00000355481.8	c.7304G>T	p.Arg2435Leu	missense_variant	Exon 45 of 105	1		ENSP00000347667.3
RYR1	ENST00000594335.5	n.755G>T		non_coding_transcript_exon_variant	Exon 6 of 49	1		ENSP00000470927.2
RYR1	ENST00000599547.6	n.7304G>T		non_coding_transcript_exon_variant	Exon 45 of 80	2		ENSP00000471601.2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000274 AC: 4 AN: 1461798 Hom.: 0 Cov.: 36 AF XY: 0.00000413 AC XY: 3 AN XY: 727198

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: 0.00000360

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

Bravo AF: 0.00000756

ClinVar

Significance: Likely pathogenic

Submissions summary: Pathogenic:4 Other:1

Revision: reviewed by expert panel

Submissions by phenotype

not provided Pathogenic:1 Other:1

Mar 21, 2023

GeneDx

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Identified in the heterozygous state in affected members of a family with central core disease; but it is unknown whether these individuals were screened for variants in other genes associated with myopathy (PMID: 23183335); Published functional studies demonstrate the variant results in increased calcium channel activity (PMIID: 28687594); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Not observed at significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 10051009, 12668474, 28687594, 19513315, 15347586, 19027160, 25214167, 23558838, 17483490, 32528171, 16835904, 16917943, 12208234, 12709367, 23183335) -

-

RYR1 database

Significance: not provided

Review Status: no classification provided

Collection Method: literature only

- -

Malignant hyperthermia, susceptibility to, 1 Pathogenic:1

Apr 07, 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 leucine at codon 2435 of the RYR1 protein, p.(Arg2435Leu). This variant was not present in a large population database (gnomAD) at the time this variant was interpreted. This variant has been reported in four unrelated individuals who have a personal or family history of a malignant hyperthermia reaction, three 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_Moderate (PMID:10051009, PMID:23558838, PMID:30236257, The UK (Leeds) MH Unit). No functional studies were identified for this variant. This variant resides in a region of RYR1 considered to be a hotspot for pathogenic variants that contribute to MHS, use PM1_Supporting to avoid overweighting with PM5 (PMID: 21118704). Another variant has been assessed as pathogenic occurs at this codon, p.(Arg2435His), PM5. A REVEL score >0.85 (0.948) supports a pathogenic status for this variant, PP3_Moderate. This variant has been classified as Likely Pathogenic. Criteria implemented: PS4_Moderate, PM1_Supporting, PM5, PP3_Moderate. -

RYR1-related disorder Pathogenic:1

Jan 26, 2025

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 leucine, which is neutral and non-polar, at codon 2435 of the RYR1 protein (p.Arg2435Leu). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with malignant hyperthermia and/or central core disease (PMID: 10051009, 12208234, 12709367, 16835904, 17483490, 19027160, 23183335, 23558838). It has also been observed to segregate with disease in related individuals. This variant is also known as Arg2436Leu. ClinVar contains an entry for this variant (Variation ID: 133196). 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 80%. Experimental studies have shown that this missense change affects RYR1 function (PMID: 19027160, 28687594). This variant disrupts the p.Arg2435 amino acid residue in RYR1. Other variant(s) that disrupt this residue have been determined to be pathogenic (internal data). 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. -

Malignant hyperthermia of anesthesia Pathogenic:1

Oct 27, 2023

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The p.Arg2435Leu variant in RYR1 has been reported in the heterozygous state in at least five individuals with malignant hyperthermia susceptibility (MHS; Barone 1999 PMID: 10051009, Galli 2002 PMID: 12208234, Tammaro 2003 PMID: 12709367, Brandom 2013 PMID: 23558838). Additionally, one heterozygous parent of a homozygous individual affected with central core disease (CCD) showed no evidence of the disease, though it is unclear to which anesthesia they were exposed to (Ghassemi 2009 PMID: 19027160). This variant was absent from large population studies (gnomAD, v.3.1.2). In vitro functional studies provide conflicting evidence regarding the impact of this variant on protein function (Dirksen 2004 PMID: 15347586, Ghassemi 2009 PMID: 19027160, Chen 2017 PMID: 28687594). Computational prediction tools and conservation analyses suggest that this variant may impact the protein. This variant resides in a region of RYR1 where variants are statistically more likely to be disease associated for MHS (Laclennan 2010, PMID: 21118704, ClinGen MHS expert panel). Another variant involving this codon (p.Arg2435His) has been identified in individuals with MHS and is classified as pathogenic by this laboratory. Additionally, it has been classified as likely pathogenic on April 7, 2023 by the ClinGen-approved Malignant Hyperthermia Susceptibility Variant Curation Expert Panel (Variation ID: 133196). In summary, although additional studies are required to fully establish its clinical significance, this variant meets criteria to be classified as likely pathogenic for autosomal dominant malignant hyperthermia. ACMG/AMP Criteria applied: PS4_Moderate, PM2_Supporting, PP3, PM5. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.95
BayesDel_addAF	Pathogenic	0.55	D
BayesDel_noAF	Pathogenic	0.56
CADD	Uncertain	24
DANN	Uncertain	0.99
DEOGEN2	Pathogenic	0.86	.;D
Eigen	Uncertain	0.63
Eigen_PC	Uncertain	0.52
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Pathogenic	1.0	D;D
M_CAP	Pathogenic	0.76	D
MetaRNN	Pathogenic	0.99	D;D
MetaSVM	Pathogenic	1.1	D
MutationAssessor	Uncertain	2.6	M;M
PrimateAI	Pathogenic	0.83	D
PROVEAN	Pathogenic	-6.6	D;D
REVEL	Pathogenic	0.95
Sift	Uncertain	0.0010	D;D
Polyphen		1.0	D;D
Vest4		0.81
MutPred		0.93		Gain of catalytic residue at R2435 (P = 0.0649);Gain of catalytic residue at R2435 (P = 0.0649);
MVP		0.95
MPC		0.38
ClinPred		1.0	D
GERP RS		4.0
Varity_R		0.68
gMVP		0.92

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

Other links and lift over

dbSNP: rs28933396; hg19: chr19-38990637;