rs193922797

Variant names:

• chr19-38496901-G-A
• rs193922797
• NM_000540.3:c.6838G>A

Your query was ambiguous. Multiple possible variants found:

• chr19-38496901-G-A
• chr19-38496901-G-T

Variant summary

Our verdict is Likely pathogenic. Variant got 6 ACMG points: 6P and 0B. PM1 PS3_Moderate PS4_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
• Clinical Significance: Likely pathogenic reviewed by expert panel P:12 U:4 O:1
• Conservation: PhyloP100: 7.53

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 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 rank	MANE	Protein	UniProt
RYR1	NM_000540.3	c.6838G>A	p.Val2280Ile	missense_variant	Exon 42 of 106	ENST00000359596.8	NP_000531.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
RYR1	ENST00000359596.8	c.6838G>A	p.Val2280Ile	missense_variant	Exon 42 of 106	5	NM_000540.3	ENSP00000352608.2
RYR1	ENST00000355481.8	c.6838G>A	p.Val2280Ile	missense_variant	Exon 42 of 105	1		ENSP00000347667.3
RYR1	ENST00000594335.5	n.289G>A		non_coding_transcript_exon_variant	Exon 3 of 49	1		ENSP00000470927.2
RYR1	ENST00000599547.6	n.6838G>A		non_coding_transcript_exon_variant	Exon 42 of 80	2		ENSP00000471601.2

Frequencies

GnomAD3 genomes AF: 0.0000394 AC: 6 AN: 152202 Hom.: 0 Cov.: 32

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: 6 AN: 250004 Hom.: 0 AF XY: 0.0000148 AC XY: 2 AN XY: 135562

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: 93 AN: 1461194 Hom.: 0 Cov.: 32 AF XY: 0.0000647 AC XY: 47 AN XY: 726898

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: 6 AN: 152202 Hom.: 0 Cov.: 32 AF XY: 0.0000403 AC XY: 3 AN XY: 74364

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.: 0

Bravo AF: 0.0000604

ExAC AF: 0.0000330 AC: 4

EpiCase AF: 0.00

EpiControl AF: 0.0000593

ClinVar

Significance: Likely pathogenic

Submissions summary: Pathogenic:12 Uncertain:4 Other:1

Revision: reviewed by expert panel

Submissions by phenotype

Malignant hyperthermia, susceptibility to, 1 Pathogenic:6

Sep 19, 2023

Color Diagnostics, LLC DBA Color Health

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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. -

May 20, 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 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. -

Sep 24, 2024

All of Us Research Program, National Institutes of Health

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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. -

Mar 31, 2025

Institute of Human Genetics, University of Leipzig Medical Center

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Criteria applied: PS3_MOD,PS4_MOD,PM1 -

Jul 17, 2014

Division of Human Genetics, Children's Hospital of Philadelphia

Significance: Likely pathogenic

Review Status: no assertion criteria provided

Collection Method: research

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. -

Dec 02, 2024

Institute of Human Genetics, Clinical Exome/Genome Diagnostics Group, University Hospital Bonn

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

PS3_mod, PS4_mod, PM1_mod -

not provided Pathogenic:2 Uncertain:3 Other:1

-

RYR1 database

Significance: not provided

Review Status: no classification provided

Collection Method: literature only

- -

Feb 16, 2024

GeneDx

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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) -

Sep 14, 2022

Revvity Omics, Revvity

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Feb 09, 2024

Clinical Genetics Laboratory, Skane University Hospital Lund

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Nov 01, 2024

CeGaT Center for Human Genetics Tuebingen

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

RYR1: PM1, PS3:Moderate, PS4:Moderate, PM2:Supporting -

Sep 03, 2021

Athena Diagnostics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

RYR1-related disorder Pathogenic:2

Jan 06, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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; internal data). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 133172). 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: 36208971). For these reasons, this variant has been classified as Pathogenic. -

Sep 20, 2024

PreventionGenetics, part of Exact Sciences

Significance: Likely pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

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. -

Malignant hyperthermia of anesthesia Pathogenic:1

Jul 25, 2023

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.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. -

King Denborough syndrome;C1850674:Congenital multicore myopathy with external ophthalmoplegia;C2930980:Malignant hyperthermia, susceptibility to, 1;C5830701:Central core myopathy Pathogenic:1

Jun 18, 2024

Fulgent Genetics, Fulgent Genetics

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

not specified Uncertain:1

Feb 02, 2017

Genetic Services Laboratory, University of Chicago

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.26
BayesDel_addAF	Pathogenic	0.26	D
BayesDel_noAF	Pathogenic	0.24
CADD	Uncertain	25
DANN	Uncertain	0.98
DEOGEN2	Uncertain	0.67	.;D
Eigen	Uncertain	0.53
Eigen_PC	Uncertain	0.58
FATHMM_MKL	Uncertain	0.91	D
LIST_S2	Pathogenic	0.99	D;D
M_CAP	Benign	0.085	D
MetaRNN	Uncertain	0.55	D;D
MetaSVM	Pathogenic	0.81	D
MutationAssessor	Uncertain	2.1	M;M
PrimateAI	Uncertain	0.70	T
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	T
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

Other links and lift over

dbSNP: rs193922797; hg19: chr19-38987541;