rs1801086

Positions:

• chr19-38446710-G-A
• chr19-38446710-G-C
• chr19-38446710-G-T

Variant summary

Our verdict is Likely pathogenic. Variant got 10 ACMG points: 11P and 1B. BS2_Supporting PM1 PP1 PS3_Moderate PS4 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 Glycine with Arginine at codon 248 of the RYR1 protein, p.(Gly248Arg), c.742G>A. This variant is not present in a large population database (gnomAD) at the time this variant was interpreted. This variant has been reported in 10 unrelated individuals who have a personal or family history of a malignant hyperthermia reaction, 8 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, PMID:23558838, PMID:11575529, PMID:1354642). This variant has been identified in 1 individual with negative IVCT/CHCT results, BS2_Moderate. Functional studies in HEK293 cells show an increased sensitivity to RYR1 agonists, PS3_Moderate, (PMID:9334205, PMID:26115329). This variant resides in a region of RYR1 considered to be a hotspot for pathogenic variants that contribute to MHS, PM1 (PMID:21118704). This variant segregates with MHS in three individuals, PP1 (PMID:1354642, PMID:19454545). A REVEL score >0.85 (0.889) supports a pathogenic status for this variant, PP3_Moderate. Based on using Bayes to combine criteria this variant is assessed as Likely Pathogenic, (PMID:29300386). Criteria implemented: PS3_Moderate, PS4, PM1, PP1, PP3_Moderate, BS2_Moderate. LINK:https://erepo.genome.network/evrepo/ui/classification/CA024797/MONDO:0007783/012

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000034 (0 hom.)
• Consequence: RYR1 NM_000540.3 missense
• Clinical Significance: Likely pathogenic reviewed by expert panel P:5 O:2
• Conservation: PhyloP100: 7.59

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 10 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.
• BS2: 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.742G>A	p.Gly248Arg	missense_variant	9/106	ENST00000359596.8	NP_000531.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
RYR1	ENST00000359596.8	c.742G>A	p.Gly248Arg	missense_variant	9/106	5	NM_000540.3	ENSP00000352608.2
RYR1	ENST00000355481.8	c.742G>A	p.Gly248Arg	missense_variant	9/105	1		ENSP00000347667.3
RYR1	ENST00000599547.6	n.742G>A		non_coding_transcript_exon_variant	9/80	2		ENSP00000471601.2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000342 AC: 5 AN: 1461702 Hom.: 0 Cov.: 31 AF XY: 0.00000138 AC XY: 1 AN XY: 727154

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: 0.0000116

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000360

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

ClinVar

Significance: Likely pathogenic

Submissions summary: Pathogenic:5 Other:2

Revision: reviewed by expert panel

Submissions by phenotype

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

Pathogenic, criteria provided, single submitter	clinical testing	Institute of Human Genetics Munich, Klinikum Rechts Der Isar, TU München	Nov 09, 2020	- -
Likely pathogenic, reviewed by expert panel	curation	ClinGen Malignant Hyperthermia Susceptibility Variant Curation Expert Panel, ClinGen	Apr 07, 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 Glycine with Arginine at codon 248 of the RYR1 protein, p.(Gly248Arg), c.742G>A. This variant is not present in a large population database (gnomAD) at the time this variant was interpreted. This variant has been reported in 10 unrelated individuals who have a personal or family history of a malignant hyperthermia reaction, 8 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, PMID:23558838, PMID:11575529, PMID:1354642). This variant has been identified in 1 individual with negative IVCT/CHCT results, BS2_Moderate. Functional studies in HEK293 cells show an increased sensitivity to RYR1 agonists, PS3_Moderate, (PMID:9334205, PMID:26115329). This variant resides in a region of RYR1 considered to be a hotspot for pathogenic variants that contribute to MHS, PM1 (PMID: 21118704). This variant segregates with MHS in three individuals, PP1 (PMID:1354642, PMID:19454545). A REVEL score >0.85 (0.889) supports a pathogenic status for this variant, PP3_Moderate. Based on using Bayes to combine criteria this variant is assessed as Likely Pathogenic, (PMID: 29300386). Criteria implemented: PS3_Moderate, PS4, PM1, PP1, PP3_Moderate, BS2_Moderate. -
risk factor, no assertion criteria provided	literature only	OMIM	Aug 01, 1992	- -

not provided Pathogenic:1 Other:1

Pathogenic, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	Oct 23, 2015	- -
not provided, no classification provided	literature only	Leiden Muscular Dystrophy (RYR1)	-	- -

RYR1-related disorder Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Jan 02, 2024

This sequence change replaces glycine, which is neutral and non-polar, with arginine, which is basic and polar, at codon 248 of the RYR1 protein (p.Gly248Arg). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individuals with malignant hyperthermia susceptibility (PMID: 1354642, 11575529, 15448513, 18564801, 19648156, 23558838). ClinVar contains an entry for this variant (Variation ID: 12965). 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: 9334205, 9873004, 27857962). For these reasons, this variant has been classified as Pathogenic. -

Malignant hyperthermia of anesthesia Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Jun 11, 2020

Two different single nucleotide variants (c.742G>C and c.742G>A) resulting in the same missense change, p.Gly248Arg, have been reported in at least 14 heterozygous individuals with malignant hyperthermia susceptibility with 9 segregations in affected relatives (Brandom 2013, Broman 2015, Broman 2009, Abolkhair 2011, Carpenter 2009, Robinson 2006, Gillard 1992, Gillies 2008, Miller 2018, Sei 2004). This variant was absent from large population studies. In one study, 3 nonsegregations (genotype negative, phenotype positive) were observed in one family; though, limited details on the affected relatives were provided (Miller 2018) and in vitro contracture testing sometimes results in false positives. This variant is reported in ClinVar by the PharmGKB expert panel as a known malignant hyperthermia variant with evidence level 1A (Variation ID 12965). One in vitro functional study suggested abnormal protein function (Sato 2010). In vitro studies investigating a nearby variant, Gly249Arg, found caffeine and halothane sensitivity of intracellular Ca2+ release in one study, and similar resting cytoplasmic Ca2+ concentration in another study (Tong 1997, 1999). Computational prediction tools and conservation analysis suggest an impact to the protein. In summary, while there is some conflicting evidence in the reported nonsegregations, there is significant evidence to support that this variant is likely pathogenic for autosomal dominant malignant hyperthermia susceptibility. ACMG/AMP criteria applied: PS4_Moderate, PP1_Strong, PM2, PS3_Supporting, PP3, BS4_Supporting. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.60
BayesDel_addAF	Pathogenic	0.43	D
BayesDel_noAF	Pathogenic	0.38
CADD	Uncertain	25
DANN	Uncertain	1.0
DEOGEN2	Pathogenic	0.81	.;D
Eigen	Uncertain	0.67
Eigen_PC	Uncertain	0.57
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Uncertain	0.97	D;D
M_CAP	Pathogenic	0.46	D
MetaRNN	Pathogenic	0.98	D;D
MetaSVM	Uncertain	0.72	D
MutationAssessor	Uncertain	2.6	M;M
PrimateAI	Uncertain	0.74	T
PROVEAN	Pathogenic	-5.4	D;D
REVEL	Pathogenic	0.89
Sift	Uncertain	0.0040	D;D
Polyphen		1.0	D;D
Vest4		0.81
MutPred		0.93		Gain of solvent accessibility (P = 0.0171);Gain of solvent accessibility (P = 0.0171);
MVP		0.98
MPC		1.1
ClinPred		1.0	D
GERP RS		4.5
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.49
gMVP		0.63

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: rs1801086; hg19: chr19-38937350; COSMIC: COSV62101123;