Variant 19-38500643-G-A details in Genebe, Genetics Data Aggregator

ACMG classification

Classification made for transcript

Verdict is Pathogenic. Variant got 13 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 linkuse as main transcript	c.7361G>A	p.Arg2454His	missense_variant	46/106	ENST00000359596.8	NP_000531.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
RYR1	ENST00000359596.8 linkuse as main transcript	c.7361G>A	p.Arg2454His	missense_variant	46/106	5	NM_000540.3	ENSP00000352608	A2	P21817-1
RYR1	ENST00000355481.8 linkuse as main transcript	c.7361G>A	p.Arg2454His	missense_variant	46/105	1		ENSP00000347667	P4	P21817-2
RYR1	ENST00000594335.5 linkuse as main transcript	c.815G>A	p.Arg272His	missense_variant, NMD_transcript_variant	7/49	1		ENSP00000470927
RYR1	ENST00000599547.6 linkuse as main transcript	c.7361G>A	p.Arg2454His	missense_variant, NMD_transcript_variant	46/80	2		ENSP00000471601

Frequencies

GnomAD3 genomes

Cov.:

32

GnomAD3 exomes

AF:

0.00000796

AC:

2

AN:

251210

Hom.:

0

AF XY:

0.00000736

AC XY:

1

AN XY:

135878

show subpopulations

Gnomad AFR exome

AF:

0.0000616

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00000881

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00000684

AC:

10

AN:

1461498

Hom.:

0

Cov.:

31

AF XY:

0.00000825

AC XY:

6

AN XY:

727048

show subpopulations

Gnomad4 AFR exome

AF:

0.0000299

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:

0.00000719

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

Cov.:

32

ExAC

AF:

0.00000824

AC:

1

EpiCase

AF:

0.00

EpiControl

AF:

0.0000593

ClinVar

Significance: Pathogenic; drug response

Submissions summary: Pathogenic:14Other:8

Revision: reviewed by expert panel

LINK: link

Submissions by phenotype

Malignant hyperthermia, susceptibility to, 1

Pathogenic:7

Pathogenic, no assertion criteria provided	research	deCODE genetics, Amgen	Jul 21, 2023	The variant NM_000540.3:c.7361G>A (chr19:38500643) in RYR1 was detected in 1 heterozygote out of 58K WGS Icelanders (MAF= 0,001%). This variant has been reported in ClinVar previously as pathogenic and is one of the diagnostic MH variants (https://www.emhg.org/diagnostic-mutations). Based on ACMG criteria (PS3, PM2, PP3, PP4, PP5_Strong) this variant classifies as pathogenic. -
Pathogenic, criteria provided, single submitter	clinical testing	Human Genome Sequencing Center Clinical Lab, Baylor College of Medicine	Jan 15, 2018	This c.7361G>A (p.Arg2454His) variant in exon 46 of the RYR1 gene has been reported in multiple individuals with susceptibility to malignant hyperthermia that was diagnosed either by a well-defined laboratory diagnostic test or patients developed malignant hyperthermia crisis during anesthesia (PMID: 16163667, 19648156, 10051009, 20301565). Independently performed functional assays also support the pathogenicity of this variant (PMID, 19191333, 16163667, 27586648). Moreover, European Malignant Hyperthermia Group (EMHG) has categorized this variant as diagnostic for susceptibility to malignant hyperthermia https://emhg.org/genetics/mutations-in-ryr1/. The c.7361G>A (p.Arg2454His) variant in the RYR1 gene is classified as pathogenic . -
Pathogenic, reviewed by expert panel	curation	ClinGen Malignant Hyperthermia Susceptibility Variant Curation Expert Panel, ClinGen	Mar 19, 2021	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 histidine at codon 2454 of the RYR1 protein, p.(Arg2454His). The maximum allele frequency for this variant among the six major gnomAD populations is AFR: 0.000062, a frequency consistent with pathogenicity for MHS. This variant has been reported in 34 unrelated individuals who have a personal or family history of a malignant hyperthermia reaction, all 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, 12059893, 16163667, 24433488, 11575529, 10051009, 10823104, 17081152, 20618998, 21455645, 23460944, 23558838, 25960145). This variant has been identified in an individual with a negative IVCT/CHCT result, BS2_Moderate (PMID: 30236257). Functional studies in HEK293 cells show an increased sensitivity to RYR1 agonists, PS3_Moderate (PMID: 27586648). An ex vivo assay in patient derived immortalized lymphoblastoid cells also shows an increased sensitivity to RYR1 agonists (PMID: 19191333). 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 at least 11 individuals/families PP1_Strong (PMID: 12059893, 10051009). A REVEL score >0.85 (0.923) supports a pathogenic status for this variant, PP3_Moderate. Based on using Bayes to combine criteria this variant is assessed as Pathogenic, (PMID: 29300386). Criteria implemented: PS3_Moderate, PS4, PM1, PP1_Strong, PP3_Moderate, BS2_Moderate. -
Pathogenic, criteria provided, single submitter	clinical testing	Baylor Genetics	Dec 10, 2022	- -
Pathogenic, criteria provided, single submitter	clinical testing	All of Us Research Program, National Institutes of Health	Aug 28, 2023	This missense variant replaces arginine with histidine at codon 2454 of the RYR1 protein. Computational prediction suggests that this variant may have deleterious impact on protein structure and function (internally defined REVEL score threshold >= 0.7, PMID: 27666373). A functional study has shown that this variant causes increased cellular sensitivity to caffeine compared to wild-type RYR1 (PMID: 16163667). This variant occurs in a region of the RYR1 protein that is considered to be a hotspot for pathogenic variants that contribute to malignant hyperthermia susceptibility (PMID: 21118704). This variant has been reported in over 25 families and/or individuals affected with malignant hyperthermia susceptibility (PMID: 12709367, 15448513, 16163667, 17081152, 19648156, 20681998, 21455645, 24433488, 25960145, 26951757) and has been reported to segregate with disease in over ten families (PMID: 30236257). This variant has been identified in 2/251210 chromosomes in the general population by the Genome Aggregation Database (gnomAD). Based on the available evidence, this variant is classified as Pathogenic. -
Pathogenic, criteria provided, single submitter	clinical testing	Color Diagnostics, LLC DBA Color Health	Jun 21, 2023	This missense variant replaces arginine with histidine at codon 2454 of the RYR1 protein. Computational prediction suggests that this variant may have deleterious impact on protein structure and function (internally defined REVEL score threshold >= 0.7, PMID: 27666373). A functional study has shown that this variant causes increased cellular sensitivity to caffeine compared to wild-type RYR1 (PMID: 16163667). This variant occurs in a region of the RYR1 protein that is considered to be a hotspot for pathogenic variants that contribute to malignant hyperthermia susceptibility (PMID: 21118704). This variant has been reported in over 25 families and/or individuals affected with malignant hyperthermia susceptibility (PMID: 12709367, 15448513, 16163667, 17081152, 19648156, 20681998, 21455645, 24433488, 25960145, 26951757) and has been reported to segregate with disease in over ten families (PMID: 30236257). This variant has been identified in 2/251210 chromosomes in the general population by the Genome Aggregation Database (gnomAD). Based on the available evidence, this variant is classified as Pathogenic. -
Pathogenic, criteria provided, single submitter	clinical testing	Institute of Human Genetics, University of Leipzig Medical Center	Jul 28, 2021	- -

not provided

Pathogenic:4Other:1

Pathogenic, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Jun 01, 2022	- -
not provided, no classification provided	literature only	Leiden Muscular Dystrophy (RYR1)	-	- -
Pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Jun 21, 2024	Reported previously, in the heterozygous state, as a pathogenic variant associated with malignant hyperthermia (PMID: 10051009, 12059893, 19648156); B-lymphocytes from individuals with the R2454H variant displayed an increased extracellular acidification rate compared with wild-type cells, suggesting that the R2454H variant causes increased calcium channel activity (PMID: 19191333); Not observed at significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 28325813, 26951757, 19648156, 31206373, 34462577, 19191333, 27586648, 28682948, 28687594, 12059893, 30236257, 30499100, 30788618, 32174957, 31447099, 17081152, 37937776, 10051009, 12668474, 33767344) -
Pathogenic, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	Mar 11, 2016	- -
Pathogenic, criteria provided, single submitter	clinical testing	Revvity Omics, Revvity	Oct 05, 2021	- -

Central core myopathy

Pathogenic:1

Pathogenic, no assertion criteria provided

curation

GeneReviews

May 11, 2010

- -

RYR1-related disorder

Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Jan 27, 2024

This sequence change replaces arginine, which is basic and polar, with histidine, which is basic and polar, at codon 2454 of the RYR1 protein (p.Arg2454His). This variant is present in population databases (rs118192122, gnomAD 0.007%). This missense change has been observed in individuals with malignant hyperthermia susceptibility (MHS) (PMID: 10051009, 12059893, 19191333, 19648156). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 65980). 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: 19191333, 19648156). This variant disrupts the p.Arg2454 amino acid residue in RYR1. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 10612851, 12411788, 16163667). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. For these reasons, this variant has been classified as Pathogenic. -

Malignant hyperthermia of anesthesia

Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

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

Jun 11, 2024

Variant summary: RYR1 c.7361G>A (p.Arg2454His) results in a non-conservative amino acid change in the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 8e-06 in 251210 control chromosomes. c.7361G>A has been reported in the literature in the heterozygous state in multiple individuals affected with autosomal dominant Malignant Hyperthermia Susceptibility (example, Barone_1999, Carpenter_2009, Miller_2018), and segregated with disease among several related individuals. These data indicate that the variant is very likely to be associated with disease. Multiple functional studies have shown this variant causes enhanced ryanodine binding and decreased the Ca2+ threshold required for spontaneous muscle contraction (example, Chen_2017, Murayama_2016). The following publications have been ascertained in the context of this evaluation (PMID: 10051009, 19648156, 28687594, 30236257, 27586648). ClinVar contains an entry for this variant (Variation ID: 65980). Based on the evidence outlined above, the variant was classified as pathogenic. -

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

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.85

BayesDel_addAF

Pathogenic

0.43

D

BayesDel_noAF

Pathogenic

0.56

CADD

Pathogenic

27

DANN

Uncertain

1.0

DEOGEN2

Pathogenic

0.86

.;D

Eigen

Pathogenic

0.80

Eigen_PC

Pathogenic

0.71

FATHMM_MKL

Pathogenic

0.98

D

LIST_S2

Pathogenic

1.0

D;D

M_CAP

Pathogenic

0.61

D

MetaRNN

Pathogenic

0.99

D;D

MetaSVM

Pathogenic

1.1

D

MutationAssessor

Uncertain

2.6

M;M

MutationTaster

Benign

1.0

D;D;D

PrimateAI

Pathogenic

0.81

D

PROVEAN

Pathogenic

-4.5

D;D

REVEL

Pathogenic

0.92

Sift

Pathogenic

0.0

D;D

Polyphen

1.0

D;D

Vest4

0.84

MutPred

0.93

Loss of MoRF binding (P = 0.0603);Loss of MoRF binding (P = 0.0603);

MVP

1.0

MPC

0.46

ClinPred

0.99

D

GERP RS

4.0

Varity_R

0.62

gMVP

0.93

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.

19-38500643-G-A

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