rs193922797

Positions:

Variant summary

Our verdict is Likely pathogenic. Variant got 6 ACMG points: 6P and 0B. PM1PS3_ModeratePS4_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 valine with isoleucine at codon 2280 of the RYR1 protein, p.(Val2280Ile). The maximum allele frequency for this variant among the six major gnomAD populations is NFE: 0.000035, a frequency consistent with pathogenicity for MHS. This variant has been reported in three unrelated individuals who have a personal or family history of a malignant hyperthermia reaction, two 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:30864471, PMID:30236257; MHIU Toronto - MH proband CGS 45). Functional studies in HEK293 cells show an increased sensitivity to RYR1 agonists, PS3_Moderate (PMID:36208971). 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 0.641 supports neither a pathogenic nor a benign status for this variant. This variant has been classified as a Likely Pathogenic. Criteria implemented: PS3_Moderate, PS4_Moderate, PM1. LINK:https://erepo.genome.network/evrepo/ui/classification/CV133172/MONDO:0007783/012

Frequency

Genomes: 𝑓 0.000039 ( 0 hom., cov: 32)

Exomes 𝑓: 0.000064 ( 0 hom. )

Consequence

RYR1
NM_000540.3 missense

Scores

Clinical Significance

Likely pathogenic reviewed by expert panel P:9U:6O:1

Conservation

PhyloP100: 7.53

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 Likely_pathogenic. Variant got 6 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.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
RYR1	NM_000540.3 linkuse as main transcript	c.6838G>A	p.Val2280Ile	missense_variant	42/106	ENST00000359596.8	NP_000531.2	P21817-1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	UniProt
RYR1	ENST00000359596.8 linkuse as main transcript	c.6838G>A	p.Val2280Ile	missense_variant	42/106	5	NM_000540.3	ENSP00000352608.2	P21817-1
RYR1	ENST00000355481.8 linkuse as main transcript	c.6838G>A	p.Val2280Ile	missense_variant	42/105	1		ENSP00000347667.3	P21817-2
RYR1	ENST00000594335.5 linkuse as main transcript	n.289G>A		non_coding_transcript_exon_variant	3/49	1		ENSP00000470927.2	M0R014
RYR1	ENST00000599547.6 linkuse as main transcript	n.6838G>A		non_coding_transcript_exon_variant	42/80	2		ENSP00000471601.2	M0R127

Frequencies

GnomAD3 genomes

AF:

0.0000394

AC:

AN:

152202

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000241

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:

0.0000735

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000240

AC:

AN:

250004

Hom.:

AF XY:

0.0000148

AC XY:

AN XY:

135562

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.0000290

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.0000463

Gnomad NFE exome

AF:

0.0000354

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000636

AC:

AN:

1461194

Hom.:

Cov.:

AF XY:

0.0000647

AC XY:

AN XY:

726898

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.0000447

Gnomad4 ASJ exome

AF:

0.0000383

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.0000758

Gnomad4 NFE exome

AF:

0.0000728

Gnomad4 OTH exome

AF:

0.0000828

GnomAD4 genome

AF:

0.0000394

AC:

AN:

152202

Hom.:

Cov.:

AF XY:

0.0000403

AC XY:

AN XY:

74364

show subpopulations

Gnomad4 AFR

AF:

0.0000241

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:

0.0000735

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.0000502

Hom.:

Bravo

AF:

0.0000604

ExAC

AF:

0.0000330

AC:

EpiCase

AF:

0.00

EpiControl

AF:

0.0000593

ClinVar

Significance: Likely pathogenic

Submissions summary: Pathogenic:9Uncertain:6Other:1

Revision: reviewed by expert panel

LINK: link

Submissions by phenotype

not provided

Pathogenic:2Uncertain:3Other:1

Uncertain significance, criteria provided, single submitter	clinical testing	Athena Diagnostics	Sep 03, 2021	- -
not provided, no classification provided	literature only	Leiden Muscular Dystrophy (RYR1)	-	- -
Likely pathogenic, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Nov 01, 2024	RYR1: PM1, PS3:Moderate, PS4:Moderate, PM2:Supporting -
Uncertain significance, criteria provided, single submitter	clinical testing	GeneDx	Feb 16, 2024	Reported in one family affected with malignant hyperthermia; however, familial segregation information was not provided (PMID: 30236257); Reported in two unrelated individuals and multiple affected individuals within one family with malignant hyperthermia susceptibility; however, this variant did not segregate with all affected individuals in this family (PMID: 36208971, 12208234, 30864471); Reported in two unrelated individuals with rhabdomyolysis; one individual was also affected with muscle cramps and elevated CK levels (PMID: 27431030, 30788618); Reported in a patient with muscle weakness and cramps, chronically elevated CK, heat intolerance, and an episode of hyperthermia and leg stiffness who inherited the variant from their mother with a history of multiple uncomplicated general anesthetics (PMID: 31559918); Published functional studies suggest this variant leads to hypersensitivity of the RYR1 channel (PMID: 36208971); In silico analysis supports that this missense variant does not alter protein structure/function; Not observed at significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 16835904, 16115682, 12208234, 27431030, 20301325, 12668474, 33767344, 36208971, 31559918, 30864471, 28007021, 30788618, 30236257) -
Uncertain significance, criteria provided, single submitter	clinical testing	Revvity Omics, Revvity	Sep 14, 2022	- -
Likely pathogenic, criteria provided, single submitter	clinical testing	Clinical Genetics Laboratory, Skane University Hospital Lund	Feb 09, 2024	- -

Malignant hyperthermia, susceptibility to, 1

Pathogenic:4Uncertain:1

Likely pathogenic, criteria provided, single submitter	clinical testing	Color Diagnostics, LLC DBA Color Health	Sep 19, 2023	This missense variant replaces valine with isoleucine at codon 2280 of the RYR1 protein. Computational prediction is inconclusive regarding the impact of this variant on protein structure and function (internally defined REVEL score threshold 0.5 < inconclusive < 0.7, PMID: 27666373). Although functional studies have not been reported for this variant, it occurs in a region of RYR1 considered to be a hotspot for pathogenic variants that contribute to malignant hyperthermia susceptibility (PMID: 21118704). This variant has been reported in at least 4 families or individuals affected with malignant hyperthermia susceptibility (PMID: 16835904, 30236257, 30864471, 36208971, 36208971, ClinVar: SCV001810122.1). It has been shown that this variant segregates with malignant hyperthermia susceptibility in 8 individuals of 1 family (PMID: 36208971). This variant has been identified in 6/250004 chromosomes in the general population by the Genome Aggregation Database (gnomAD). Based on the available evidence, this variant is classified as Likely Pathogenic. -
Uncertain significance, criteria provided, single submitter	clinical testing	Institute of Human Genetics, University of Leipzig Medical Center	Jan 01, 2019	- -
Likely pathogenic, no assertion criteria provided	research	Division of Human Genetics, Children's Hospital of Philadelphia	Jul 17, 2014	This test identified one heterozygous variant (c.6838G>A;p.Val2280Ile) in the RYR1 gene (see Table IIIA). Variants in this gene have been associated with increased risk of malignant hyperthermia (autosomal dominant) and different types of congenital myopathies - central core disease (autosomal dominant or autosomal recessive), multiminicore disease (autosomal recessive), congenital fiber type disproportion (autosomal dominant or autosomal recessive). The RYR1 gene encodes for calcium channels that play a critical role in the movement of skeletal muscles. Risk for malignant hyperthermia is predominantly associated with the use of general anesthesia with specific anesthetics, which can trigger an episode (hypermetabolism, rhabdomyolysis, hyperkalaemia, cardiac arrhythmia). A very small number of individuals with malignant hyperthermia susceptibility appear to be at risk for heat stroke or exercise-induced rhabdomyolysis,). Malignant hyperthermia has been reported to occur in individuals without anesthetic exposure. If an episode is untreated, it can be life threatening. Alternative anesthetic treatments are available for known individuals susceptible to malignant hyperthermia. This variant has been reported in a family susceptible to malignant hyperthermia based on biochemical testing (Galli et al 2002,PMID: 12208234; Galli et al. 2006, PMID: 16835904), and computational evidence is also suggestive of this variant being a pathogenic variant. -
Likely pathogenic, criteria provided, single submitter	clinical testing	All of Us Research Program, National Institutes of Health	Sep 24, 2024	The c.6838G>A variant, located on the exon 42 of the RYR1 gene, replaces valine with isoleucine at codon 2280 of the RYR1 protein (p.Val2280Ile). This missense change has been observed in three individuals with personal or family histories of malignant hyperthermia syndrome (MHS), with positive in vitro contracture test (IVCT) or caffeine halothane contracture test (CHCT) (PMID: 12208234, 30236257, 30864471). This missense variant is located in a mutational hotspot region that is known to contribute to MHS (PMID: 21118704). A functional study in HEK293 cells showed increased sensitivity to RYR1 agonists (PMID: 36208971). Computational prediction (REVEL score 0.641) suggests that this variant may not have deleterious impact on protein structure and function. This variant has been classified as likely pathogenic by the expert panel in ClinVar (ID:133172). This variant is rare (6/250004 chromosomes) in the general population database, gnomAD. For these reasons, the c.6838G>A (p.Val2280Ile) variant in the RYR1 gene is classified as likely pathogenic. -
Likely pathogenic, reviewed by expert panel	curation	ClinGen Malignant Hyperthermia Susceptibility Variant Curation Expert Panel, ClinGen	May 20, 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 valine with isoleucine at codon 2280 of the RYR1 protein, p.(Val2280Ile). The maximum allele frequency for this variant among the six major gnomAD populations is NFE: 0.000035, a frequency consistent with pathogenicity for MHS. This variant has been reported in three unrelated individuals who have a personal or family history of a malignant hyperthermia reaction, two 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:30864471, PMID:30236257; MHIU Toronto - MH proband CGS 45). Functional studies in HEK293 cells show an increased sensitivity to RYR1 agonists, PS3_Moderate (PMID:36208971). 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 0.641 supports neither a pathogenic nor a benign status for this variant. This variant has been classified as a Likely Pathogenic. Criteria implemented: PS3_Moderate, PS4_Moderate, PM1. -

RYR1-related disorder

Pathogenic:2

Likely pathogenic, no assertion criteria provided	clinical testing	PreventionGenetics, part of Exact Sciences	Sep 20, 2024	The RYR1 c.6838G>A variant is predicted to result in the amino acid substitution p.Val2280Ile. This variant has been reported in individuals with autosomal dominant RYR1-related disorders, including multiple individuals with malignant hyperthermia (MH) susceptibility confirmed via in vitro contracture testing (IVCT; see, for example, Galli et al. 2002. PubMed ID: 12208234; Scalco et al. 2016. PubMed ID: 27431030; Hudig et al. 2019. PubMed ID: 30864471). It segregated with disease in eight MH-susceptible individuals from one family, although two additional family members who were negative for this variant were also MH-susceptible (White et al. 2022. PubMed ID: 36208971). While this variant has only been reported in the literature in relation to autosomal dominant conditions, at PreventionGenetics, it has been observed with a second RYR1 variant in individuals being tested for autosomal recessive myopathy (Internal Data). In vitro experimental studies indicate this variant impacts protein function (White et al. 2022. PubMed ID: 36208971). It is reported in 0.0046% of alleles in individuals of European (Finnish) descent in gnomAD and has been classified as likely pathogenic by the ClinGen Malignant Hyperthermia Susceptibility Variant Curation Expert Panel (https://www.ncbi.nlm.nih.gov/clinvar/variation/133172/). This variant occurs in a region of the gene considered to be a hotspot for MH or central core disease (Witherspoon and Meilleur. 2016. PubMed ID: 27855725). This variant is interpreted as likely pathogenic. -
Pathogenic, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Dec 28, 2023	This sequence change replaces valine, which is neutral and non-polar, with isoleucine, which is neutral and non-polar, at codon 2280 of the RYR1 protein (p.Val2280Ile). This variant is present in population databases (rs193922797, gnomAD 0.004%). This missense change has been observed in individual(s) with clinical features of autosomal dominant RYR1-related conditions and/or malignant hyperthermia susceptibility (PMID: 12208234, 30236257, 30788618, 31559918, 36208971; Invitae). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 133172). 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: 36208971). For these reasons, this variant has been classified as Pathogenic. -

Malignant hyperthermia of anesthesia

Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

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

Jul 25, 2023

Variant summary: RYR1 c.6838G>A (p.Val2280Ile) results in a 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 2.4e-05 in 250004 control chromosomes. c.6838G>A has been reported in the literature in multiple individuals affected with Malignant Hyperthermia Susceptibility supported by a diagnostic in vitro contracture test (IVCT) or caffeine halothane contracture test (CHCT) result (example, Galli_2002, Scalco_2016, Oberg_2016, Knulman_2019, Hudig_2019, Sadhasivam_2019, White_2022). Of these, in one report of families with this variant, eight transmissions of the variant allele and 2 transmissions of the reference allele to affected Malignant Hyperthermia Susceptible individuals was reported (White_2022). This study included this variant among RYR-1 disease causing variants for diagnostic use managed by the European Malignant Hyperthermia Group. These data indicate that the variant is very likely to be associated with disease. One publication reports experimental evidence evaluating an impact on protein function, demonstrating hypersensitivity to an RyR1 agonist in calcium release assays (White_2022). Eight submitters have cited clinical-significance assessments for this variant to ClinVar after 2014. Multiple submitters to include the ClinGen Malignant Hyperthermia Susceptibility Variant Curation Expert Panel, reported the variant with conflicting assessments (VUS, n=6; LP, n=2). Based on the evidence outlined above, the variant was classified as likely pathogenic. -

not specified

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Genetic Services Laboratory, University of Chicago

Feb 02, 2017

- -

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

Oct 21, 2021

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.26

BayesDel_addAF

Pathogenic

0.26

BayesDel_noAF

Pathogenic

0.24

CADD

Uncertain

DANN

Uncertain

0.98

DEOGEN2

Uncertain

0.67

.;D

Eigen

Uncertain

0.53

Eigen_PC

Uncertain

0.58

FATHMM_MKL

Uncertain

0.91

LIST_S2

Pathogenic

0.99

D;D

M_CAP

Benign

0.085

MetaRNN

Uncertain

0.55

D;D

MetaSVM

Pathogenic

0.81

MutationAssessor

Uncertain

2.1

M;M

PrimateAI

Uncertain

0.70

PROVEAN

Benign

-0.69

N;N

REVEL

Uncertain

0.64

Sift

Uncertain

0.020

D;D

Polyphen

0.94

P;P

Vest4

0.58

MVP

1.0

MPC

0.26

ClinPred

0.41

GERP RS

5.0

Varity_R

0.12

gMVP

0.42

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

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