Variant 19-38444211-C-T details in Genebe, Genetics Data Aggregator

ACMG classification

Classification made for transcript

Verdict is Pathogenic. Variant got 15 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.

PM5

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 linkuse as main transcript	c.487C>T	p.Arg163Cys	missense_variant	6/106	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.487C>T	p.Arg163Cys	missense_variant	6/106	5	NM_000540.3	ENSP00000352608.2	P21817-1
RYR1	ENST00000355481.8 linkuse as main transcript	c.487C>T	p.Arg163Cys	missense_variant	6/105	1		ENSP00000347667.3	P21817-2
RYR1	ENST00000599547.6 linkuse as main transcript	n.487C>T		non_coding_transcript_exon_variant	6/80	2		ENSP00000471601.2	M0R127

Frequencies

GnomAD3 genomes

Cov.:

32

GnomAD4 exome

AF:

0.00000137

AC:

2

AN:

1461862

Hom.:

0

Cov.:

32

AF XY:

0.00000138

AC XY:

1

AN XY:

727230

show subpopulations

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:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00000180

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

Cov.:

32

Bravo

AF:

0.00000378

ClinVar

Significance: Pathogenic; drug response

Submissions summary: Pathogenic:8Other:10

Revision: reviewed by expert panel

LINK: link

Submissions by phenotype

Malignant hyperthermia, susceptibility to, 1

Pathogenic:3Other:1

risk factor, no assertion criteria provided	literature only	OMIM	Jul 11, 2001	- -
Pathogenic, criteria provided, single submitter	clinical testing	Institute of Human Genetics, University of Leipzig Medical Center	Dec 10, 2024	Criteria applied: PS3,PS4,PP1_STR,PM1_SUP,PM5_SUP,PP3 -
Pathogenic, reviewed by expert panel	curation	ClinGen Malignant Hyperthermia Susceptibility Variant Curation Expert Panel, ClinGen	Mar 29, 2022	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 arginine with cysteine at codon 163 of the RYR1 protein p.(Arg163Cys). This variant is not present in a large population databases (gnomAD). This variant has been reported in over 40 unrelated individuals who have a personal or family history of a malignant hyperthermia reaction and a positive in vitro contracture test (IVCT) or caffeine halothane contracture test (CHCT) result (when the proband was unavailable for testing a positive diagnostic test result in a mutation positive relative was counted), PS4 (PMID:30236257, PMID:12151923, PMID:16163667, PMID:8220423, PMID:11575529, PMID:12059893, PMID:23558838 and others). This variant has been identified in 1 individual with negative IVCT/CHCT results, BS2_Moderate (PMID:30236257). Functional studies in HEK293 cells show an increased sensitivity to RYR1 agonists. A knock-in mouse model supports pathogenicity of this variant demonstrating a malignant hyperthermia reaction in response to agonist, as well ex vivo studies show increased response to agonist with increased calcium release, PS3 (PMID:20461000, PMID:9334205, PMID:17122579). Another variant assessed as likely pathogenic occurs at this codon, p.(Arg163Leu), PM5_Supporting. This variant resides in a region of RYR1 considered to be a hotspot for pathogenic variants that contribute to MHS, use PM1_Supporting to avoid overweighting with PM5 (PMID: 21118704). This variant segregates with MHS over seven individuals, PP1_Strong (PMID:30236257, PMID:12059893, PMID:7889656). A REVEL score > 0.85 (0.959) supports pathogenicity, PP3_Moderate. Based on using Bayes to combine criteria this variant is assessed as Pathogenic, (PMID: 29300386). Criteria implemented: PS4, PS3, PM1_Supporting, PM5_Supporting, PP1_Strong, PP3_Moderate, BS2_Moderate. -
Pathogenic, criteria provided, single submitter	clinical testing	All of Us Research Program, National Institutes of Health	May 06, 2024	The c.487C>T (p.Arg163Cys) variant, located on the exon 6 of the RYR1 gene, replaces arginine with cysteine at codon 163 of the RYR1 protein (p.Arg163Cys). This variant has been observed in >40 individuals with personal or family histories of a malignant hyperthermia reaction, positive in vitro contracture test (IVCT) or caffeine halothane contracture test (CHCT) (PMID:30236257, 12151923, 16163667, 8220423, 11575529, 12059893, 23558838 and others). This variant is located in a mutational hot spot region that contributes to malignant hyperthermia (PMID: 21118704). Functional studies in HEK293 cells show an increased sensitivity to RYR1 agonists. A knock-in mouse model supports pathogenicity of this variant demonstrating a malignant hyperthermia reaction in response to agonist, as well ex vivo studies show increased response to agonist with increased calcium release (PMID:20461000, 9334205, 17122579). Computational prediction (REVEL >0.85) suggests that this variant may have deleterious impact on protein structure and function. This variant is absent in the control population (gnomAD). This variant is reported in ClinVar and classified pathogenic by the expert panel (ID: 12967). Another variant affecting the same amino acid, c.488G>T (p.Arg163Leu), has also been classified as pathogenic by the expert panel in ClinVar (ID:133137). Therefore, the c.487C>T (p.Arg163Cys) variant in the RYR1 gene is classified as pathogenic. -

not provided

Pathogenic:3Other:1

Pathogenic, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Aug 30, 2021	The RYR1 c.487C>T; p.Arg163Cys variant (rs118192161) is reported in individuals with malignant hyperthermia (MH) and central core disease (CCD) and segregates with MH and CCD in several families (Carpenter 2009, O'Brien 1995, Quane 1993). The variant is listed in the ClinVar database (Variation ID: 12967) but is absent from general population databases (Exome Variant Server, Genome Aggregation Database), indicating it is not a common polymorphism. The arginine at codon 163 is moderately conserved, and computational analyses predict that this variant is deleterious (REVEL: 0.959). Additionally, experimental studies show that this variant alters protein function in vitro and in vivo, including in a mouse model of this variant (Avila 2001, Feng 2011, Tong 1997). Based on available information, this variant is considered to be pathogenic. References: Avila G and Dirksen RT. Functional effects of central core disease mutations in the cytoplasmic region of the skeletal muscle ryanodine receptor. J Gen Physiol. 2001 Sep;118(3):277-90. PMID: 11524458. Carpenter D et al. Genetic variation in RYR1 and malignant hyperthermia phenotypes. Br J Anaesth. 2009 Oct;103(4):538-48. PMID: 19648156. Feng W et al. Functional and biochemical properties of ryanodine receptor type 1 channels from heterozygous R163C malignant hyperthermia-susceptible mice. Mol Pharmacol. 2011 Mar;79(3):420-31. PMID: 21156754. O'Brien RO et al. Exclusion of defects in the skeletal muscle specific regions of the DHPR alpha 1 subunit as frequent causes of malignant hyperthermia. J Med Genet. 1995 Nov;32(11):913-4. PMID: 8592342. Quane KA et al. Mutations in the ryanodine receptor gene in central core disease and malignant hyperthermia. Nat Genet. 1993 Sep;5(1):51-5. PMID: 8220423. Tong J et al. Caffeine and halothane sensitivity of intracellular Ca2+ release is altered by 15 calcium release channel (ryanodine receptor) mutations associated with malignant hyperthermia and/or central core disease. J Biol Chem. 1997 Oct 17;272(42):26332-9. PMID: 9334205. -
Pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Sep 10, 2023	Published functional studies demonstrate a damaging effect as R163C results in hypersensitivity to halothane and increased calcium release (Censier et al., 1998; Chen et al., 2017); 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; Also known as p.R164C; This variant is associated with the following publications: (PMID: 19541610, 20461000, 21156754, 20479108, 17122579, 32826313, 23459219, 12732639, 11524458, 9873004, 9334205, 8592342, 12411788, 28687594, 7889656, 9502764, 30499100, 19648156, 8220423, 21965348, 30236257, 12124989, 35741838, 35428369, 32403337, 33767344) -
Pathogenic, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	Nov 14, 2016	- -
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 08, 2024

This sequence change replaces arginine, which is basic and polar, with cysteine, which is neutral and slightly polar, at codon 163 of the RYR1 protein (p.Arg163Cys). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individuals with autosomal dominant malignant hyperthermia (MH) and central core disease (CCD) (PMID: 8220423, 8592342, 19648156). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 12967). 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 with a positive predictive value of 95%. Experimental studies have shown that this missense change affects RYR1 function (PMID: 9334205, 11524458, 21156754). For these reasons, this variant has been classified as Pathogenic. -

Malignant hyperthermia of anesthesia

Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Oct 17, 2019

The p.Arg163Cys variant in RYR1 has been reported in at least 15 individuals with malignant hyperthermia and segregated with disease in at least 7 affected individuals from several families (Broman 2011, Carpenter 2009, Tobin 2001, Quane 1993, Wappler 2001, Monnier 2002). Of note, this variant has been associated with central core disease and rhabdomyolysis, and in one individual with heat stroke. This variant was absent from large population studies but has been reported in ClinVar (Variation ID 12967). Computational prediction tools and conservation analyses suggest that this variant may impact the protein, though this information is not predictive enough to determine pathogenicity. In vitro functional studies support an impact on protein function (Carpenter 2009). Another variant involving this codon (p.Arg163His) has been identified in individuals with malignant hyperthermia and has been reported in ClinVar (ClinVar ID 635269). In summary, this variant meets criteria to be classified as pathogenic for autosomal dominant malignant hyperthermia. ACMG/AMP Criteria applied: PS4, PP1_Strong, PM2, PS3_Moderate, PP3 -

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

Central core myopathy

Other:1

risk factor, no assertion criteria provided

literature only

OMIM

Jul 11, 2001

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.89

BayesDel_addAF

Pathogenic

0.53

D

BayesDel_noAF

Pathogenic

0.52

CADD

Pathogenic

28

DANN

Uncertain

1.0

DEOGEN2

Pathogenic

0.92

.;D

Eigen

Uncertain

0.59

Eigen_PC

Uncertain

0.50

FATHMM_MKL

Benign

0.54

D

LIST_S2

Pathogenic

1.0

D;D

M_CAP

Pathogenic

0.62

D

MetaRNN

Pathogenic

0.98

D;D

MetaSVM

Pathogenic

1.1

D

MutationAssessor

Pathogenic

3.0

M;M

PrimateAI

Pathogenic

0.90

D

PROVEAN

Pathogenic

-6.4

D;D

REVEL

Pathogenic

0.96

Sift

Pathogenic

0.0

D;D

Polyphen

1.0

D;D

Vest4

0.86

MutPred

0.86

Loss of disorder (P = 0.0278);Loss of disorder (P = 0.0278);

MVP

0.99

MPC

1.2

ClinPred

0.99

D

GERP RS

4.3

Varity_R

0.64

gMVP

0.92

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.

19-38444211-C-T

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