rs118192140

Positions:

chr19-38573304-C-T

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 3P and 1B. PP3_ModerateBS3_SupportingPM1_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 threonine with methionine at codon 4709 of the RYR1 protein, p.(Thr4709Met). The maximum allele frequency for this variant among the six major gnomAD populations is SAS: 0.00003, a frequency consistent with pathogenicity for MHS. This variant has been reported in individuals with recessive myopathies (PMID:17033962, PMID:21062345, PMID:22473935). A knock-in mouse model does not demonstrate a response to isoflurane in the heterozygous state, this is considered evidence against pathogenicity for autosomal dominantly inherited MH, BS_Supporting (PMID:31107960). This variant resides in a region of RYR1 considered to be a hotspot for pathogenic variants that contribute to MHS, PM1_Sup (PMID:21118704). A REVEL score >0.85 (0.901) supports a pathogenic status for this variant, PP3_Moderate. This variant has been classified as a Variant of Unknown Significance. Criteria implemented: PM1_Supporting, PP3_Moderate, BS3_Supporting. LINK:https://erepo.genome.network/evrepo/ui/classification/CA024104/MONDO:0007783/012

Frequency

Genomes: 𝑓 0.000046 ( 0 hom., cov: 31)

Exomes 𝑓: 0.000025 ( 0 hom. )

Consequence

RYR1
NM_000540.3 missense

Scores

Clinical Significance

Uncertain significance reviewed by expert panel P:12U:3O:1

Conservation

PhyloP100: 7.88

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 2 ACMG points.

PM1

PP3

BS3

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
RYR1	NM_000540.3 linkuse as main transcript	c.14126C>T	p.Thr4709Met	missense_variant	96/106	ENST00000359596.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
RYR1	ENST00000359596.8 linkuse as main transcript	c.14126C>T	p.Thr4709Met	missense_variant	96/106	5	NM_000540.3	A2	P21817-1

Frequencies

GnomAD3 genomes

AF:

0.0000460

AC:

AN:

152110

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00144

Gnomad EAS

AF:

0.000193

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00

Gnomad OTH

AF:

0.000478

GnomAD3 exomes

AF:

0.0000441

AC:

AN:

249700

Hom.:

AF XY:

0.0000370

AC XY:

AN XY:

135098

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.0000290

Gnomad ASJ exome

AF:

0.000796

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.0000327

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00000890

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000246

AC:

AN:

1460964

Hom.:

Cov.:

AF XY:

0.0000303

AC XY:

AN XY:

726752

show subpopulations

Gnomad4 AFR exome

AF:

0.0000299

Gnomad4 AMR exome

AF:

0.0000224

Gnomad4 ASJ exome

AF:

0.000919

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.0000348

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00000450

Gnomad4 OTH exome

AF:

0.0000332

GnomAD4 genome

AF:

0.0000460

AC:

AN:

152228

Hom.:

Cov.:

AF XY:

0.0000538

AC XY:

AN XY:

74404

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00144

Gnomad4 EAS

AF:

0.000193

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.00

Gnomad4 OTH

AF:

0.000473

Alfa

AF:

0.000111

Hom.:

Bravo

AF:

0.0000378

ExAC

AF:

0.0000165

AC:

ClinVar

Significance: Uncertain significance

Submissions summary: Pathogenic:12Uncertain:3Other:1

Revision: reviewed by expert panel

LINK: link

Submissions by phenotype

not provided

Pathogenic:3Other:1

not provided, no classification provided	literature only	Leiden Muscular Dystrophy (RYR1)	-	- -
Pathogenic, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	Mar 26, 2018	- -
Pathogenic, criteria provided, single submitter	clinical testing	Revvity Omics, Revvity	Mar 15, 2022	- -
Pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Dec 16, 2022	Reported as a putative dominant variant but inheritance uncertain in a patient with features of of an RYR1-related myopathy who also had other variants in the RYR1 gene, without clear segregation information (Zhou et al., 2007; Klein et al., 2012); Published functional studies demonstrate decreased protein expression compared to controls in muscle and monoallelic expression of the T4709M allele, suggesting epigenetic silencing of the other RYR1 allele in an affected individual (Zhou et al., 2007); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 26332594, 17483490, 22473935, 23919265, 26633545, 30611313, 17033962, 32403337, 31980526, 33087929, 21062345, 31107960) -

Malignant hyperthermia, susceptibility to, 1

Uncertain:3

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. -
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 threonine with methionine at codon 4709 of the RYR1 protein, p.(Thr4709Met). The maximum allele frequency for this variant among the six major gnomAD populations is SAS: 0.00003, a frequency consistent with pathogenicity for MHS. This variant has been reported in individuals with recessive myopathies (PMID:17033962, PMID:21062345, PMID:22473935). A knock-in mouse model does not demonstrate a response to isoflurane in the heterozygous state, this is considered evidence against pathogenicity for autosomal dominantly inherited MH, BS_Supporting (PMID:31107960). This variant resides in a region of RYR1 considered to be a hotspot for pathogenic variants that contribute to MHS, PM1_Sup (PMID: 21118704). A REVEL score >0.85 (0.901) supports a pathogenic status for this variant, PP3_Moderate. This variant has been classified as a Variant of Unknown Significance. Criteria implemented: PM1_Supporting, PP3_Moderate, BS3_Supporting. -
Uncertain significance, criteria provided, single submitter	clinical testing	All of Us Research Program, National Institutes of Health	Nov 30, 2023	This missense variant replaces threonine with methionine at codon 4709 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 using genetically engineered mice showed that mice homozygous for this variant are hypersensitive to isoflurane and experience an increase in core body temperature similar to malignant hyperthermia susceptible mice, but at a slower rate. Further, the study showed that mice heterozygous for this variant were not hypersensitive to isoflurane and did not experience an increase in core temperature compared to wild-type mice (PMID: 31107960). This variant has not been reported in individuals affected with autosomal dominant malignant hyperthermia in the literature, although it is associated with other phenotype(s) (ClinVar variation ID: 65996). This variant has been identified in 12/281074 chromosomes in the general population by the Genome Aggregation Database (gnomAD). Due to insufficient evidence, this variant is classified as a Variant of Uncertain Significance for autosomal dominant malignant hyperthermia. -

RYR1-related disorder

Pathogenic:2

Pathogenic, criteria provided, single submitter	clinical testing	Invitae	Jan 16, 2024	This sequence change replaces threonine, which is neutral and polar, with methionine, which is neutral and non-polar, at codon 4709 of the RYR1 protein (p.Thr4709Met). This variant is present in population databases (rs118192140, gnomAD 0.09%). This missense change has been observed in individuals with autosomal recessive congenital myopathy (PMID: 17483490, 23919265, 31055738; Invitae). ClinVar contains an entry for this variant (Variation ID: 65996). 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: 1743490). For these reasons, this variant has been classified as Pathogenic. -
Likely pathogenic, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Nov 12, 2018	The RYR1 c.14126C>T (p.Thr4709Met) variant has been reported in at least five studies and is found in a total of five patients with RYR1-related disorders including central code disease, multiminicore disease, and neuromuscular disease including four in a compound heterozygous state and one in a heterozygous state (Zhou et al. 2007; Bevilacqua et al. 2011; Amburgey et al. 2013; Vill et al. 2017; Todd et al. 2018). The p.Thr4709Met variant was absent from 300 controls and is reported at a frequency of 0.000888 in the Ashkenazi Jewish population of the Genome Aggregation Database. Zhou et al. (2007) demonstrated greatly reduced levels of RYR1 protein in skeletal muscles of patients in whom the p.Thr4709Met heterozygous variant was expressed in the background of a second non-transcribed allele. Based on the evidence, the p.Thr4709Met variant is classified as likely pathogenic RYR1-related disorders. This variant was observed by ICSL as part of a predisposition screen in an ostensibly healthy population. -

Congenital multicore myopathy with external ophthalmoplegia

Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Baylor Genetics

Dec 23, 2013

This variant has been previously reported as disease-causing and was found once in our laboratory in trans with another pathogenic variant [R2241X] in a 25-year-old female with motor delays, tinnitus, vertigo, central hypotonia, peripheral hypertonia, pes cavus, dysmorphisms, microcephaly, ophthalmoplegia, supraventricular tachycardia, scoliosis, lordosis -

Central core myopathy

Pathogenic:1

Pathogenic, no assertion criteria provided

curation

GeneReviews

May 11, 2010

- -

Central core myopathy;C1850674:Congenital multicore myopathy with external ophthalmoplegia

Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

Suma Genomics

- -

Central core myopathy;C1840365:King Denborough syndrome;C1850674:Congenital multicore myopathy with external ophthalmoplegia;C2930980:Malignant hyperthermia, susceptibility to, 1

Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Center for Genomics, Ann and Robert H. Lurie Children's Hospital of Chicago

Mar 30, 2021

RYR1 NM_000540.2 exon 96 p.Thr4709Met (c.14126C>T): This variant has been reported in the literature in the compound heterozygous state or with monoallelic expression in at least 3 individuals with congenital myopathies (Zhou 2007 PMID:17483490, Bevilacqua 2011 PMID:21062345, Amburgey 2013 PMID:23919265). This variant is present in 0.08% (9/10346) of Ashkenazi Jewish alleles in the Genome Aggregation Database (http://gnomad.broadinstitute.org/variant/19-39063944-C-T). Please note, disease causing variants may be present in control databases at low frequencies, reflective of the general population, carrier status, and/or variable expressivity. This variant is present in ClinVar, with several labs classifying this variant as pathogenic or likely pathogenic (Variation ID:65996). Evolutionary conservation and computational predictive tools suggest that this variant may impact the protein. Additionally, western blot studies on skeletal muscle tissue have demonstrated decreased protein expression, further supporting a deleterious effect of this variant (Zhou 2007 PMID:17483490). In summary, this variant is classified as pathogenic based on the data above. -

Congenital myopathy with fiber type disproportion;C0751951:Central core myopathy;C1850674:Congenital multicore myopathy with external ophthalmoplegia;C2930980:Malignant hyperthermia, susceptibility to, 1

Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

Fulgent Genetics, Fulgent Genetics

Oct 31, 2018

- -

Congenital myopathy

Pathogenic:1

Likely pathogenic, criteria provided, single submitter

curation

Broad Center for Mendelian Genomics, Broad Institute of MIT and Harvard

Jun 19, 2024

The heterozygous p.Thr4709Met variant in RYR1 was identified by our study, in the compound heterozygous state, along with a likely pathogenic variant, in 1 individual with autosomal recessive congenital myopathy. The p.Thr4709Met variant in RYR1 has been reported in at least 2 individuals with congenital myopathy (PMID: 21062345, 30155738), and has been identified in 0.1% (29/29576) of Ashkenazi Jewish chromosomes by the Genome Aggregation Database (gnomAD, http://gnomad.broadinstitute.org; dbSNP ID: rs118192140). Although this variant has been seen in the general population in a heterozygous state, its frequency is not high enough to rule out a pathogenic role. This variant has also been reported in ClinVar (Variation ID: 65996) and has been interpreted as pathogenic or likely pathogenic by multiple submitters for congenital myopathy, and as a variant of uncertain significance by the ClinGen Malignant Hyperthermia Susceptibility Variant Curation Expert Panel. Of the 3 affected individuals, 3 were compound heterozygotes that carried reported pathogenic/likely pathogenic variant in trans or with unknown phase, which increases the likelihood that the p.Thr4709Met variant is pathogenic (PMID: 30155738). Animal models in mice have shown that this variant causes autosomal recessive congenital myopathy (PMID: 31107960). Computational prediction tools and conservation analyses suggest that this variant may impact the protein, though this information is not predictive enough to determine pathogenicity. The number of missense variants reported in RYR1 in the general population is lower than expected, suggesting there is little benign variation in this gene and slightly increasing the possibility that a missense variant in this gene may not be tolerated. In summary, although additional studies are required to fully establish its clinical significance, this variant is likely pathogenic for autosomal recessive congenital myopathy. ACMG/AMP Criteria applied: PP3_moderate, PM3, PS3_moderate, PP2 (Richards 2015). -

Abnormality of the musculature

Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

Kariminejad - Najmabadi Pathology & Genetics Center

Jul 10, 2021

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Uncertain

0.45

BayesDel_addAF

Pathogenic

0.43

BayesDel_noAF

Pathogenic

0.47

CADD

Uncertain

DANN

Benign

0.97

DEOGEN2

Pathogenic

0.81

.;D

Eigen

Pathogenic

0.70

Eigen_PC

Uncertain

0.65

FATHMM_MKL

Uncertain

0.97

LIST_S2

Pathogenic

0.99

D;D

M_CAP

Pathogenic

0.56

MetaRNN

Pathogenic

0.75

D;D

MetaSVM

Pathogenic

1.1

MutationAssessor

Uncertain

2.3

.;M

MutationTaster

Benign

1.0

D;D;D

PrimateAI

Pathogenic

0.83

PROVEAN

Pathogenic

-4.7

D;D

REVEL

Pathogenic

0.90

Sift

Uncertain

0.0010

D;D

Polyphen

1.0

D;D

Vest4

0.77

MVP

0.96

MPC

0.60

ClinPred

0.94

GERP RS

4.5

Varity_R

0.53

gMVP

0.84

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.

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