19-38496265-C-T

Variant names:

Variant summary

Our verdict is Uncertain significance. The variant received 5 ACMG points: 5P and 0B. PP1_ModeratePS4_SupportingPM1

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 alanine with valine at codon 2200 of the RYR1 protein, p.Ala2200Val. The maximum allele frequency for this variant among the six major gnomAD populations is EAS: 0.00015, 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, 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), apply PS4_Supporting due to EAS MAF of 0.00015 (PMID:15731587, PMID:21455645, PMID:30236257 ). 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, PM1 (PMID:21118704). This variant segregates with MHS in 6 individuals (PMID:21455645, PMID:16835904, personal communication). A REVEL score of 0.564 supports neither a pathogenic nor a benign status for this variant. This variant has been classified as a Variant of Unknown Significance. Criteria implemented: PS4_Supporting, PM1, PP1_Moderate. LINK:https://erepo.genome.network/evrepo/ui/classification/CA024615/MONDO:0007783/012

Frequency

Genomes: 𝑓 0.000020 ( 0 hom., cov: 32)

Exomes 𝑓: 0.000052 ( 0 hom. )

Consequence

RYR1
NM_000540.3 missense

Scores

Clinical Significance

Uncertain significance reviewed by expert panel P:3U:4O:1

Conservation

PhyloP100: 3.40

Publications

2 publications found

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 Gene-Disease associations (from GenCC):

malignant hyperthermia, susceptibility to, 1
Inheritance: AD Classification: DEFINITIVE, STRONG Submitted by: Labcorp Genetics (formerly Invitae), ClinGen, Genomics England PanelApp, Ambry Genetics
congenital multicore myopathy with external ophthalmoplegia
Inheritance: AR Classification: DEFINITIVE, STRONG Submitted by: G2P, Genomics England PanelApp
RYR1-related myopathy
Inheritance: AR, AD Classification: DEFINITIVE Submitted by: ClinGen
central core myopathy
Inheritance: AD, AR Classification: STRONG, SUPPORTIVE Submitted by: Labcorp Genetics (formerly Invitae), Orphanet, Genomics England PanelApp
King-Denborough syndrome
Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
malignant hyperthermia of anesthesia
Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
autosomal recessive centronuclear myopathy
Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet
benign Samaritan congenital myopathy
Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet
congenital myopathy with myasthenic-like onset
Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet
lethal multiple pterygium syndrome
Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

RYR1 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Uncertain_significance. The variant received 5 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.

PP1

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 link	c.6599C>T	p.Ala2200Val	missense_variant	Exon 40 of 106	ENST00000359596.8	NP_000531.2	P21817-1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
RYR1	ENST00000359596.8 link	c.6599C>T	p.Ala2200Val	missense_variant	Exon 40 of 106	5	NM_000540.3	ENSP00000352608.2		P21817-1

Frequencies

GnomAD3 genomes

AF:

0.0000197

AC:

AN:

152162

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.000193

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000294

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.0000398

AC:

AN:

251220

AF XY:

0.0000515

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.0000289

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.000163

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000440

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000520

AC:

AN:

1461686

Hom.:

Cov.:

AF XY:

0.0000523

AC XY:

AN XY:

727122

show subpopulations

African (AFR)

AF:

0.0000597

AC:

AN:

33480

American (AMR)

AF:

0.0000447

AC:

AN:

44724

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26134

East Asian (EAS)

AF:

0.0000504

AC:

AN:

39698

South Asian (SAS)

AF:

0.0000348

AC:

AN:

86258

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53222

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5768

European-Non Finnish (NFE)

AF:

0.0000549

AC:

AN:

1112008

Other (OTH)

AF:

0.0000993

AC:

AN:

60394

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.459

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.0000197

AC:

AN:

152162

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

74326

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

41448

American (AMR)

AF:

0.00

AC:

AN:

15274

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3472

East Asian (EAS)

AF:

0.000193

AC:

AN:

5178

South Asian (SAS)

AF:

0.00

AC:

AN:

4824

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10616

Middle Eastern (MID)

AF:

0.00

AC:

AN:

316

European-Non Finnish (NFE)

AF:

0.0000294

AC:

AN:

68028

Other (OTH)

AF:

0.00

AC:

AN:

2094

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.492

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.0000564

Hom.:

Bravo

AF:

0.0000491

ExAC

AF:

0.0000412

AC:

EpiCase

AF:

0.0000545

EpiControl

AF:

0.000119

ClinVar

Significance: Uncertain significance

Submissions summary: Pathogenic:3Uncertain:4Other:1

Revision: reviewed by expert panel

LINK: link

Submissions by phenotype

RYR1-related disorder

Pathogenic:1Uncertain:1

Sep 30, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This sequence change replaces alanine, which is neutral and non-polar, with valine, which is neutral and non-polar, at codon 2200 of the RYR1 protein (p.Ala2200Val). This variant is present in population databases (rs193922791, gnomAD 0.02%). This missense change has been observed in individual(s) with malignant hyperthermia susceptibility (PMID: 15731587, 16835904, 21455645). ClinVar contains an entry for this variant (Variation ID: 133162). 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 not expected to disrupt RYR1 protein function with a negative predictive value of 95%. For these reasons, this variant has been classified as Pathogenic. -

May 10, 2024

PreventionGenetics, part of Exact Sciences

Significance:Uncertain significance

Review Status:no assertion criteria provided

Collection Method:clinical testing

The RYR1 c.6599C>T variant is predicted to result in the amino acid substitution p.Ala2200Val. This variant has been reported in several individuals with either malignant hyperthermia (MH) events or positive in vitro muscle contracture tests, suggesting MH susceptibility (MHS) (Sambuughin et al. 2005. PubMed ID: 15731587; Galli et al. 2006. PubMed ID: 16835904; Robinson et al. 2006. PubMed ID: 16917943; Kraeva et al. 2011. PubMed ID: 21455645; Klingler et al. 2014. PubMed ID: 24433488; Miller et al. 2018. PubMed ID: 30236257). This variant was also reported in an individual with myalgia and exercise intolerance and mild myopathic findings from a muscle biopsy (Rubegni. 2019. PubMed ID: 31517061). However, in one study this variant was indicated to not segregate with MHS in a family that had a different RYR1 MH pathogenic variant detected (Zullo et al. 2009. PubMed ID: 19191333). At PreventionGenetics, we have previously observed this variant in two patients with reported MH events and an additional patient with recurrent rhabdomyolysis (internal data). However, in one of these individuals with a MH event, a different established pathogenic RYR1 variant was also detected (internal data). This variant has been reported in a large population database with 11 alleles previously (https://gnomad.broadinstitute.org/variant/19-38986905-C-T?dataset=gnomad_r2_1) and with a recent updated version it is observed in 79 alleles, which may be too common for a primary cause of an autosomal dominant disease (https://gnomad.broadinstitute.org/variant/19-38496265-C-T?dataset=gnomad_r4). This variant has been observed in individuals with another RYR1 variant (internal and literature) and may suggest it acts in more of a recessive manner. This variant is reported in ClinVar as uncertain by the ClinGen Malignant Hyperthermia Susceptibility Variant Curation Expert Panel (https://www.ncbi.nlm.nih.gov/clinvar/variation/133162/). Although we suspect this variant could possibly contribute to RYR1-related disorders, at this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence. -

Malignant hyperthermia, susceptibility to, 1

Uncertain:2

Apr 10, 2023

ClinGen Malignant Hyperthermia Susceptibility Variant Curation Expert Panel, ClinGen

Significance:Uncertain significance

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 alanine with valine at codon 2200 of the RYR1 protein, p.Ala2200Val. The maximum allele frequency for this variant among the six major gnomAD populations is EAS: 0.00015, 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, 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), apply PS4_Supporting due to EAS MAF of 0.00015 (PMID:15731587, PMID:21455645, PMID:30236257 ). 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, PM1 (PMID: 21118704). This variant segregates with MHS in 6 individuals (PMID:21455645, PMID:16835904, personal communication). A REVEL score of 0.564 supports neither a pathogenic nor a benign status for this variant. This variant has been classified as a Variant of Unknown Significance. Criteria implemented: PS4_Supporting, PM1, PP1_Moderate. -

Aug 06, 2024

All of Us Research Program, National Institutes of Health

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This missense variant replaces alanine with valine at codon 2200 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). To our knowledge, functional studies have not been reported for this variant. This variant has been reported in several individuals affected with malignant hyperthermia susceptibility (PMID: 15731587, 21455645, 30236257). One study has reported that this variant did not segregate with the malignant hyperthermia susceptibility phenotype in the pedigrees analyzed and concluded this variant might be a common polymorphism (PMID: 19191333). This variant has been identified in 11/282610 chromosomes in the general population by the Genome Aggregation Database (gnomAD). The available evidence is insufficient to determine the role of this variant in disease conclusively. Therefore, this variant is classified as a Variant of Uncertain Significance. -

not provided

Uncertain:1Other:1

RYR1 database

Significance:not provided

Review Status:no classification provided

Collection Method:literature only

- -

May 11, 2023

GeneDx

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Identified in a patient with a clinical malignant hyperthermia episode with an equivocal in vitro muscle contracture test (IVCT) (Klinger et al., 2014); Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant does not alter protein structure/function; This variant is associated with the following publications: (PMID: 30122538, 31517061, 15731587, 16835904, 16917943, 19191333, 24433488, 21455645, 12668474, 33767344) -

Malignant hyperthermia of anesthesia

Pathogenic:1

May 29, 2025

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

Significance:Likely pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Variant summary: RYR1 c.6599C>T (p.Ala2200Val) results in a non-conservative amino acid change in the encoded protein sequence. Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change. The variant allele was found at a frequency of 4e-05 in 251220 control chromosomes. This frequency is not significantly higher than estimated for a pathogenic variant in RYR1 causing Malignant Hyperthermia Susceptibility (4e-05 vs 8.8e-05), allowing no conclusion about variant significance. c.6599C>T has been observed in individuals affected with Malignant Hyperthermia Susceptibility with or without positive caffeine-halothane contracture test (Sambuughin_2025, Galli_2006, Kraeva_2011). These data indicate that the variant is likely to be associated with disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. The following publications have been ascertained in the context of this evaluation (PMID: 36833224, 16835904, 21455645, 30236257, 31517061, 15731587, 19191333). ClinVar contains an entry for this variant (Variation ID: 133162). Based on the evidence outlined above, the variant was classified as likely pathogenic. -

Central core myopathy

Pathogenic:1

Neuberg Centre For Genomic Medicine, NCGM

Significance:Likely pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

The missense variant p.A2200V in RYR1 (NM_000540.3) has been previously reported with malignant hyperthermia susceptibility in affected individuals (Kraeva N et al,Robinson R et al). The variant is present in a functional domain associated with malignant hyperthermia (Galli L et al). The variant has been submitted to ClinVar as Pathogenic/Likely Pahogenic. The p.A2200V variant is observed in 3/18,390 (0.0163%) alleles from individuals of East Asian background in gnomAD Exomes and is novel (not in any individuals) in 1000 Genomes. For these reasons, this variant has been classified as Likely Pathogenic -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.30

BayesDel_addAF

Uncertain

0.16

BayesDel_noAF

Pathogenic

0.25

CADD

Uncertain

(source)

DANN

Uncertain

1.0

DEOGEN2

Uncertain

0.51

.;D

Eigen

Benign

-0.20

Eigen_PC

Benign

-0.021

FATHMM_MKL

Uncertain

0.90

LIST_S2

Uncertain

0.88

D;D

M_CAP

Benign

0.042

MetaRNN

Pathogenic

0.91

D;D

MetaSVM

Benign

-0.32

MutationAssessor

Benign

1.5

L;L

PhyloP100

3.4

PrimateAI

Pathogenic

0.88

PROVEAN

Benign

-1.7

N;N

REVEL

Uncertain

0.56

Sift

Benign

1.0

T;T

Polyphen

0.72

P;P

Vest4

0.88

MutPred

0.87

Gain of MoRF binding (P = 0.1609);Gain of MoRF binding (P = 0.1609);

MVP

0.97

MPC

0.31

ClinPred

0.081

GERP RS

4.6

Varity_R

0.082

gMVP

0.77

Mutation Taster

=2/98

disease causing (ClinVar)

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over