19-38573304-C-T

Variant names:

• chr19-38573304-C-T
• rs118192140
• NM_000540.3:c.14126C>T

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 3P and 1B. BS3_Supporting PM1_Supporting PP3_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 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
• Clinical Significance: Uncertain significance reviewed by expert panel P:13 U:3 O:1
• Conservation: PhyloP100: 7.88

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 Uncertain_significance. Variant got 2 ACMG points.

• PM1: For more information check the summary or visit ClinGen Evidence Repository.
• PP3: For more information check the summary or visit ClinGen Evidence Repository.
• BS3: 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.14126C>T	p.Thr4709Met	missense_variant	Exon 96 of 106	ENST00000359596.8	NP_000531.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
RYR1	ENST00000359596.8	c.14126C>T	p.Thr4709Met	missense_variant	Exon 96 of 106	5	NM_000540.3	ENSP00000352608.2

Frequencies

GnomAD3 genomes AF: 0.0000460 AC: 7 AN: 152110 Hom.: 0 Cov.: 31

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: 11 AN: 249700 Hom.: 0 AF XY: 0.0000370 AC XY: 5 AN XY: 135098

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: 36 AN: 1460964 Hom.: 0 Cov.: 31 AF XY: 0.0000303 AC XY: 22 AN XY: 726752

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: 7 AN: 152228 Hom.: 0 Cov.: 31 AF XY: 0.0000538 AC XY: 4 AN XY: 74404

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.: 0

Bravo AF: 0.0000378

ExAC AF: 0.0000165 AC: 2

ClinVar

Significance: Uncertain significance

Submissions summary: Pathogenic:13 Uncertain:3 Other:1

Revision: reviewed by expert panel

Submissions by phenotype

not provided Pathogenic:3 Other:1

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RYR1 database

Significance: not provided

Review Status: no classification provided

Collection Method: literature only

- -

Oct 29, 2024

GeneDx

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Reported as a putative dominant variant but inheritance uncertain in a patient with features of an RYR1-related myopathy who also had other variants in the RYR1 gene, without clear segregation information (PMID: 22473935, 17483490); 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, 23919265, 26633545, 30611313, 17033962, 32403337, 31980526, 33087929, 35361824, 32236737, 21062345, 31107960, 22473935, 17483490, 37670077) -

Mar 26, 2018

PreventionGenetics, part of Exact Sciences

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Mar 15, 2022

Revvity Omics, Revvity

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Malignant hyperthermia, susceptibility to, 1 Uncertain:3

Apr 28, 2017

Illumina Laboratory Services, Illumina

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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. -

Apr 06, 2023

ClinGen Malignant Hyperthermia Susceptibility Variant Curation Expert Panel, ClinGen

Significance: Uncertain significance

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 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. -

Aug 06, 2024

All of Us Research Program, National Institutes of Health

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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. -

Congenital multicore myopathy with external ophthalmoplegia Pathogenic:2

Dec 23, 2013

Baylor Genetics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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 -

Jan 24, 2025

Institute of Medical Genetics and Applied Genomics, University Hospital Tübingen

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

RYR1-related disorder Pathogenic:2

Jan 30, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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; internal data). ClinVar contains an entry for this variant (Variation ID: 65996). 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) has been performed for this missense variant. However, the output from this modeling did not meet the statistical confidence thresholds required to predict the impact of this variant on RYR1 protein function. Experimental studies have shown that this missense change affects RYR1 function (PMID: 1743490). For these reasons, this variant has been classified as Pathogenic. -

Nov 12, 2018

Illumina Laboratory Services, Illumina

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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;C5830701:Central core myopathy Pathogenic:1

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Suma Genomics

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

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

Mar 30, 2021

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

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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

Oct 31, 2018

Fulgent Genetics, Fulgent Genetics

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Congenital myopathy Pathogenic:1

Jun 19, 2024

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

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: curation

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

Jul 10, 2021

Kariminejad - Najmabadi Pathology & Genetics Center

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Central core myopathy Pathogenic:1

May 11, 2010

GeneReviews

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: curation

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.45
BayesDel_addAF	Pathogenic	0.43	D
BayesDel_noAF	Pathogenic	0.47
CADD	Uncertain	25
DANN	Benign	0.97
DEOGEN2	Pathogenic	0.81	.;D
Eigen	Pathogenic	0.70
Eigen_PC	Uncertain	0.65
FATHMM_MKL	Uncertain	0.97	D
LIST_S2	Pathogenic	0.99	D;D
M_CAP	Pathogenic	0.56	D
MetaRNN	Pathogenic	0.75	D;D
MetaSVM	Pathogenic	1.1	D
MutationAssessor	Uncertain	2.3	.;M
PrimateAI	Pathogenic	0.83	D
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	D
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

Other links and lift over

dbSNP: rs118192140; hg19: chr19-39063944; COSMIC: COSV62103069; COSMIC: COSV62103069;