chr19-38512321-G-A

Position:

• chr19-38512321-G-A

Variant summary

Our verdict is Likely pathogenic. Variant got 8 ACMG points: 8P and 0B. PP1_Moderate PS3_Moderate PS4_Moderate 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 glutamic acid with lysine at codon 3104 of the RYR1 protein, p.(Arg3104Lys). 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 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), PS4_Moderate (PMID:30236257). This variant segregates with MHS in five individuals, PP1_Moderate (PMID:28403410). A functional study in HEK293 cells shows an increased sensitivity to RYR1 agonists, PS3_Moderate (PMID:28403410). This variant does not reside in a hotspot for pathogenic variants that contribute to MHS. A REVEL score >0.85 (0.869) supports a pathogenic status for this variant, PP3_Moderate. This variant has been classified as Likely Pathogenic. Criteria implemented: PS3_Moderate, PS4_Moderate, PP1_Moderate, PP3_Moderate. LINK:https://erepo.genome.network/evrepo/ui/classification/CA024976/MONDO:0007783/012

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000089 (0 hom.)
• Consequence: RYR1 NM_000540.3 missense
• Clinical Significance: Likely pathogenic; drug response reviewed by expert panel P:6 O:8
• Conservation: PhyloP100: 10.0

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 8 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.
• 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.9310G>A	p.Glu3104Lys	missense_variant	63/106	ENST00000359596.8	NP_000531.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
RYR1	ENST00000359596.8	c.9310G>A	p.Glu3104Lys	missense_variant	63/106	5	NM_000540.3	ENSP00000352608.2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD3 exomes AF: 0.00000398 AC: 1 AN: 251370 Hom.: 0 AF XY: 0.00 AC XY: 0 AN XY: 135876

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: 0.0000327

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000889 AC: 13 AN: 1461876 Hom.: 0 Cov.: 34 AF XY: 0.0000138 AC XY: 10 AN XY: 727242

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: 0.0000232

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000809

Gnomad4 OTH exome AF: 0.0000331

GnomAD4 genome Cov.: 32

ExAC AF: 0.0000165 AC: 2

ClinVar

Significance: Likely pathogenic; drug response

Submissions summary: Pathogenic:6 Other:8

Revision: reviewed by expert panel

Submissions by phenotype

not provided Pathogenic:3 Other:1

Likely pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Oct 18, 2024	Reported previously in association with malignant hyperthermia (PMID: 16917943, 28403410); Identified in patients with malignant hyperthermia susceptibility in published literature, but the individuals in this study may have additional variants in genes associated with malignant hyperthermia susceptibility (PMID: 30236257); Published functional studies demonstrate that this variant increases receptor activity and resulting calcium release compared with wild type (PMID: 28403410); 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: 20301325, 19648156, 31301762, 31589614, 16917943, 28403410, 12668474, 30236257, Rieko2022[article]) -
not provided, no classification provided	literature only	Leiden Muscular Dystrophy (RYR1)	-	- -
Likely pathogenic, criteria provided, single submitter	clinical testing	Revvity Omics, Revvity	Aug 07, 2019	- -
Likely pathogenic, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	Dec 28, 2015	- -

Malignant hyperthermia, susceptibility to, 1 Pathogenic:2

Likely pathogenic, reviewed by expert panel	curation	ClinGen Malignant Hyperthermia Susceptibility Variant Curation Expert Panel, ClinGen	Apr 06, 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 glutamic acid with lysine at codon 3104 of the RYR1 protein, p.(Arg3104Lys). 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 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), PS4_Moderate (PMID: 30236257). This variant segregates with MHS in five individuals, PP1_Moderate (PMID: 28403410). A functional study in HEK293 cells shows an increased sensitivity to RYR1 agonists, PS3_Moderate (PMID: 28403410). This variant does not reside in a hotspot for pathogenic variants that contribute to MHS. A REVEL score >0.85 (0.869) supports a pathogenic status for this variant, PP3_Moderate. This variant has been classified as Likely Pathogenic. Criteria implemented: PS3_Moderate, PS4_Moderate, PP1_Moderate, PP3_Moderate. -
Likely pathogenic, criteria provided, single submitter	clinical testing	All of Us Research Program, National Institutes of Health	Jun 26, 2023	This missense variant replaces glutamic acid with lysine at codon 3104 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). A functional study in HEK239 cells has shown cells expressing this variant have increased sensitivity to RYR1 agonists compared to cells expressing wild-type RYR1 (PMID: 28403410). This variant has been reported in five individuals affected with malignant hyperthermia susceptibility (PMID: 16917943, 19648156, 28403410, 28403410, 30236257). It has been shown that this variant segregates with disease in at least 4 families (PMID: 28403410). This variant has been identified in 1/251370 chromosomes in the general population by the Genome Aggregation Database (gnomAD). Based on the available evidence, this variant is classified as Likely Pathogenic. -

RYR1-related disorder Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Apr 25, 2022

This sequence change replaces glutamic acid, which is acidic and polar, with lysine, which is basic and polar, at codon 3104 of the RYR1 protein (p.Glu3104Lys). This variant is present in population databases (rs193922832, gnomAD 0.003%). This missense change has been observed in individuals with malignant hyperthermia susceptibility (PMID: 16917943, 19648156). ClinVar contains an entry for this variant (Variation ID: 133240). 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. Experimental studies have shown that this missense change affects RYR1 function (PMID: 28403410). For these reasons, this variant has been classified as Pathogenic. -

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	Pathogenic	0.91
BayesDel_addAF	Pathogenic	0.38	D
BayesDel_noAF	Pathogenic	0.41
CADD	Uncertain	24
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.76	.;D
Eigen	Pathogenic	0.74
Eigen_PC	Pathogenic	0.70
FATHMM_MKL	Uncertain	0.93	D
LIST_S2	Pathogenic	0.98	D;D
M_CAP	Pathogenic	0.37	D
MetaRNN	Pathogenic	0.89	D;D
MetaSVM	Pathogenic	0.97	D
MutationAssessor	Benign	1.9	L;L
PrimateAI	Pathogenic	0.83	D
PROVEAN	Uncertain	-3.6	D;D
REVEL	Pathogenic	0.87
Sift	Benign	0.18	T;T
Polyphen		1.0	D;D
Vest4		0.74
MutPred		0.76		Gain of MoRF binding (P = 0.0075);Gain of MoRF binding (P = 0.0075);
MVP		1.0
MPC		0.34
ClinPred		0.94	D
GERP RS		4.4
Varity_R		0.56
gMVP		0.68

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: rs193922832; hg19: chr19-39002961; COSMIC: COSV62099148;