19-38519237-C-T

Position:

chr19-38519237-C-T

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 1P and 0B. PS4_Supporting

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 arginine with cysteine at codon 3348 of the RYR1 protein, p.(Arg3348Cys). The maximum allele frequency for this variant among the six major gnomAD populations is NFE: 0.000132, a frequency consistent with pathogenicity for MHS. This variant has been reported in an individual with a personal or family history of an MH episode and 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) (PMID:30236257), PS4_Supporting. No functional studies were identified for this variant. This variant does not reside in a hotspot for pathogenic variants that contribute to MHS. A REVEL score of 0.603 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. LINK:https://erepo.genome.network/evrepo/ui/classification/CA079715/MONDO:0007783/012

Frequency

Genomes: 𝑓 0.000079 ( 0 hom., cov: 31)

Exomes 𝑓: 0.000078 ( 0 hom. )

Consequence

RYR1
NM_000540.3 missense

Scores

Clinical Significance

Uncertain significance reviewed by expert panel U:12

Conservation

PhyloP100: 1.73

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 Uncertain_significance. Variant got 1 ACMG points.

PS4

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.10042C>T	p.Arg3348Cys	missense_variant	67/106	ENST00000359596.8	NP_000531.2	P21817-1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
RYR1	ENST00000359596.8 linkuse as main transcript	c.10042C>T	p.Arg3348Cys	missense_variant	67/106	5	NM_000540.3	ENSP00000352608.2		P21817-1

Frequencies

GnomAD3 genomes

AF:

0.0000789

AC:

AN:

152184

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:

0.000162

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000638

AC:

AN:

250976

Hom.:

AF XY:

0.0000589

AC XY:

AN XY:

135726

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.000199

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.000123

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000780

AC:

114

AN:

1461826

Hom.:

Cov.:

AF XY:

0.0000853

AC XY:

AN XY:

727220

show subpopulations

Gnomad4 AFR exome

AF:

0.0000299

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.000268

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.0000116

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.0000908

Gnomad4 OTH exome

AF:

0.0000662

GnomAD4 genome

AF:

0.0000789

AC:

AN:

152184

Hom.:

Cov.:

AF XY:

0.0000807

AC XY:

AN XY:

74350

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:

0.000162

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.0000772

Hom.:

Bravo

AF:

0.0000453

ESP6500AA

AF:

0.00

AC:

ESP6500EA

AF:

0.000233

AC:

ExAC

AF:

0.0000741

AC:

EpiCase

AF:

0.0000545

EpiControl

AF:

0.000178

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:12

Revision: reviewed by expert panel

LINK: link

Submissions by phenotype

Malignant hyperthermia, susceptibility to, 1

Uncertain:4

Uncertain significance, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Apr 28, 2017	The RYR1 c.10042C>T (p.Arg3348Cys) variant has been reported in one study in which it was found in two individuals from the same family (Kaufmann et al. 2012). The index individual was compound heterozygous for the p.Arg3348Cys variant and a second missense variant and was found to be susceptible to malignant hyperthermia based on an in vitro contracture test. In addition, her mother was heterozygous for the p.Arg3348Cys variant and exhibited malignant hyperthermia equivocal to halothane based on an in vitro contracture test. The index individual's sister was heterozygous for the other missense variant and was also susceptible to malignant hyperthermia. In the presence of halothane, cells that carried the p.Arg3348Cys variant were three times more sensitive than control cells, and in cells that carried both variants, the reaction sensitivity was increased even further. The p.Arg3348Cys variant was absent from 105 controls and is reported at a frequency of 0.00014 in the European (non-Finnish) population of the Exome Aggregation Consortium. Based on the limited evidence, the p.Arg3348Cys variant is classified as a variant of unknown significance but suspicious for pathogenicity for malignant hyperthermia susceptibility. This variant was observed by ICSL as part of a predisposition screen in an ostensibly healthy population. -
Uncertain significance, criteria provided, single submitter	clinical testing	All of Us Research Program, National Institutes of Health	Sep 23, 2024	This missense variant replaces arginine with cysteine at codon 3348 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 in patient-derived muscle cells showed cells carrying this variant were more sensitive to caffeine and halothane, but not 4-CmC, than cells carrying wild-type RYR1 (PMID: 22415532). This variant has been reported in two families affected with malignant hyperthermia susceptibility (PMID: 22415532, 30236257). One family also carried a pathogenic variant in the RYR1 gene that could explain the observed phenotype (PMID: 22415532). This variant has been identified in 19/282350 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. -
Uncertain significance, reviewed by expert panel	curation	ClinGen Malignant Hyperthermia Susceptibility Variant Curation Expert Panel, ClinGen	Apr 06, 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 arginine with cysteine at codon 3348 of the RYR1 protein, p.(Arg3348Cys). The maximum allele frequency for this variant among the six major gnomAD populations is NFE: 0.000132, a frequency consistent with pathogenicity for MHS. This variant has been reported in an individual with a personal or family history of an MH episode and 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) (PMID:30236257), PS4_Supporting. No functional studies were identified for this variant. This variant does not reside in a hotspot for pathogenic variants that contribute to MHS. A REVEL score of 0.603 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. -
Uncertain significance, criteria provided, single submitter	clinical testing	Color Diagnostics, LLC DBA Color Health	Mar 13, 2023	This missense variant replaces arginine with cysteine at codon 3348 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 in patient-derived muscle cells showed cells carrying this variant were more sensitive to caffeine and halothane, but not 4-CmC, than cells carrying wild-type RYR1 (PMID: 22415532). This variant has been reported in two families affected with malignant hyperthermia susceptibility (PMID: 22415532, 30236257). One family also carried a pathogenic variant in the RYR1 gene that could explain the observed phenotype (PMID: 22415532). This variant has been identified in 19/282350 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. -

RYR1-related disorder

Uncertain:2

Uncertain significance, no assertion criteria provided	clinical testing	PreventionGenetics, part of Exact Sciences	Mar 29, 2024	The RYR1 c.10042C>T variant is predicted to result in the amino acid substitution p.Arg3348Cys. This variant has been reported to segregate with malignant hyperthermia (MH) in a family (Kaufmann A et al 2012. PubMed ID: 22415532). However, only one individual in this family was identified with this variant alone, whereas other family members with disease harbored another known causative MH variant. A different substitution of the same amino acid (p.Arg3348His) is reported to be causative for malignant hyperthermia susceptibility (Sambuughin et al. 2005. PubMed ID: 15731587). This variant is reported in 0.019% of alleles in individuals of Ashkenazi Jewish descent in gnomAD. This variant has an interpretation of uncertain significance in ClinVar (https://www.ncbi.nlm.nih.gov/clinvar/variation/329095/). Although we suspect that this variant may be pathogenic, at this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence. -
Uncertain significance, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Nov 01, 2022	This sequence change replaces arginine, which is basic and polar, with cysteine, which is neutral and slightly polar, at codon 3348 of the RYR1 protein (p.Arg3348Cys). This variant is present in population databases (rs118204421, gnomAD 0.02%). This missense change has been observed in individual(s) with malignant hyperthermia (PMID: 22415532). ClinVar contains an entry for this variant (Variation ID: 329095). 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. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. -

Congenital multicore myopathy with external ophthalmoplegia

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Apr 28, 2017

This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). No publications were found based on this search. Allele frequency data from public databases did not allow this variant to be ruled in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance. -

Congenital myopathy with fiber type disproportion

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Centre for Mendelian Genomics, University Medical Centre Ljubljana

Sep 11, 2019

This variant was classified as: Uncertain significance. The available evidence on this variant's pathogenicity is insufficient or conflicting. The following ACMG criteria were applied in classifying this variant: PP3,PP5. -

not provided

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Revvity Omics, Revvity

Feb 24, 2023

- -

Neuromuscular disease, congenital, with uniform type 1 fiber

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jun 14, 2016

- -

Central core myopathy

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Apr 28, 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

Feb 11, 2022

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.30

BayesDel_addAF

Uncertain

0.064

BayesDel_noAF

Uncertain

0.090

CADD

Benign

DANN

Benign

0.97

DEOGEN2

Uncertain

0.76

.;D

Eigen

Uncertain

0.26

Eigen_PC

Benign

0.20

FATHMM_MKL

Uncertain

0.77

LIST_S2

Pathogenic

0.99

D;D

M_CAP

Pathogenic

0.85

MetaRNN

Pathogenic

0.91

D;D

MetaSVM

Pathogenic

0.83

MutationAssessor

Benign

1.1

L;L

PrimateAI

Uncertain

0.68

PROVEAN

Pathogenic

-4.8

D;D

REVEL

Pathogenic

0.78

Sift

Uncertain

0.0030

D;D

Polyphen

1.0

D;D

Vest4

0.77

MVP

0.99

MPC

0.41

ClinPred

0.61

GERP RS

3.5

Varity_R

0.32

gMVP

0.45

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.010

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