19-38496283-C-T

Position:

• chr19-38496283-C-T

Variant summary

Our verdict is Pathogenic. Variant got 11 ACMG points: 15P and 4B. PM1_Supporting PS4 PP3_Moderate PP1_Strong BS2 PS3_Moderate PM5

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 2206 of the RYR1 protein, p.(Thr2206Met). The maximum allele frequency for this variant among the six major gnomAD populations is EAS: 0.00005, a frequency consistent with pathogenicity for MHS. This variant has been reported in 67 unrelated individuals who have a personal or family history of a malignant hyperthermia reaction, 63 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, 24433488, 23558838, 10484775, 25735680, 25960145, 16163667, 11575529, 12220451, 12434264, 15731587, 17081152, 18505122, 22696611, 9497245, 25268394, 31559918). This variant has been identified in at least three individuals with negative IVCT/CHCT results, BS2 (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 myotubes from two related individuals showed an increased sensitivity to RYR1 agonists (PMID:12220451). 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). Another variant that has been assessed as pathogenic occurs at this codon, p.(Thr2206Arg), PM5. This variant segregates with MHS in nine individuals, PP1_Strong (PMID:12059893, 25960145). A REVEL score >0.85 (0.95) 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: PS4, PS3_Moderate, PM1_Supporting, PM5, PP1_Strong, PP3_Moderate, BS2. LINK:https://erepo.genome.network/evrepo/ui/classification/CA024622/MONDO:0007783/012

• Frequency:
  • Genomes: 𝑓 0.000039 (0 hom., cov: 32)
  • Exomes 𝑓: 0.000021 (0 hom.)
• Consequence: RYR1 NM_000540.3 missense
• Clinical Significance: Pathogenic reviewed by expert panel P:20 O:2
• Conservation: PhyloP100: 7.91

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 Pathogenic. Variant got 11 ACMG points.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
RYR1	NM_000540.3	c.6617C>T	p.Thr2206Met	missense_variant	40/106	ENST00000359596.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
RYR1	ENST00000359596.8	c.6617C>T	p.Thr2206Met	missense_variant	40/106	5	NM_000540.3	A2
RYR1	ENST00000355481.8	c.6617C>T	p.Thr2206Met	missense_variant	40/105	1		P4
RYR1	ENST00000594335.5	c.71C>T	p.Thr24Met	missense_variant, NMD_transcript_variant	1/49	1
RYR1	ENST00000599547.6	c.6617C>T	p.Thr2206Met	missense_variant, NMD_transcript_variant	40/80	2

Frequencies

GnomAD3 genomes AF: 0.0000394 AC: 6 AN: 152168 Hom.: 0 Cov.: 32

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: 0.0000943

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000588

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.0000199 AC: 5 AN: 251224 Hom.: 0 AF XY: 0.0000147 AC XY: 2 AN XY: 135792

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.0000544

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000352

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000205 AC: 30 AN: 1461714 Hom.: 0 Cov.: 32 AF XY: 0.0000165 AC XY: 12 AN XY: 727144

Gnomad4 AFR exome AF: 0.0000597

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.0000252

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000225

Gnomad4 OTH exome AF: 0.0000331

GnomAD4 genome AF: 0.0000394 AC: 6 AN: 152168 Hom.: 0 Cov.: 32 AF XY: 0.0000404 AC XY: 3 AN XY: 74322

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: 0.0000943

Gnomad4 NFE AF: 0.0000588

Gnomad4 OTH AF: 0.00

Alfa AF: 0.0000575 Hom.: 0

Bravo AF: 0.0000302

ExAC AF: 0.0000330 AC: 4

EpiCase AF: 0.00

EpiControl AF: 0.000119

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:20 Other:2

Revision: reviewed by expert panel

Submissions by phenotype

Malignant hyperthermia, susceptibility to, 1 Pathogenic:8 Other:1

Pathogenic, criteria provided, single submitter	clinical testing	Human Genome Sequencing Center Clinical Lab, Baylor College of Medicine	Jun 17, 2019	The c.6617C>T (p.Thr2206Met) variant in the RYR1 gene has been reported in multiple unrelated individuals affected with malignant hyperthermia (PMID 9497245, 12220451, 19648156) and is extremely rare in general population databases. Multiple independent in vitro experiments showed this variant is functionally damaging (PMID 12220451, 19648156, 27586648). Multiple in silico algorithms also predicted this p.Thr2206Met change to be deleterious. Therefore, this c.6617C>T (p.Thr2206Met) variant in the RYR1 gene is classified as pathogenic. -
Pathogenic, criteria provided, single submitter	clinical testing	Color Diagnostics, LLC DBA Color Health	Jan 17, 2023	This missense variant replaces threonine with methionine at codon 2206 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 HEK293 cells showed that cells expressing this variant are more sensitive to the RYR1 agonist caffeine than cells expressing wild-type RYR1 (PMID: 27586648). This variant has been reported in multiple individuals and families affected with malignant hyperthermia susceptibility (PMID: 30236257, 31206373), and it has been shown that this variant segregates with malignant hyperthermia susceptibility in several families (PMID: 9497245, 19919814, 25960145). This variant has been identified in 6/282614 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 Munich, Klinikum Rechts Der Isar, TU München	Feb 19, 2021	- -
Pathogenic, criteria provided, single submitter	clinical testing	Johns Hopkins Genomics, Johns Hopkins University	May 21, 2020	- -
risk factor, no assertion criteria provided	literature only	OMIM	Aug 01, 2002	- -
Pathogenic, criteria provided, single submitter	clinical testing	All of Us Research Program, National Institutes of Health	Dec 15, 2023	The c.6617C>T (p.Thr2206Met) variant in the RYR1 gene, that encodes ryanodine receptor 1, has been identified in numerous unrelated individuals (>50) with personal or family history of a malignant hyperthermia reaction and a positive in-vitro contracture test (IVCT) or caffeine halothane contracture test (CHCT) result (PMID: 30236257, 12059893, 24433488, 23558838, 10484775, 25735680, 25960145, 16163667, 11575529, 12220451, 12434264, 15731587, 17081152, 18505122, 22696611, 9497245, 25268394, 31559918, ClinGen Review [ClinVar ID:12977]). This variant segregates with malignant hyperthermia syndrome (MHS) in nine individuals (PMID: 12059893, 25960145).This missense variant resides in a mutational hot spot region that contributes to MHS (PMID: 21118704). A functional study in HEK293 cells shows an increased sensitivity to RYR1 agonists (PMID: 27586648). In-silico computational prediction tools suggest that the p.Thr2206Met variant may have deleterious effect on the protein function (REVEL score: 0.95). This variant has been interpreted as pathogenic by several submitters in ClinVar database including the ClinGen expert panel (ClinVar ID: 12977). Therefore, the c.6617C>T (p.Thr2206Met) variant in the RYR1 gene is classified as pathogenic. -
Pathogenic, criteria provided, single submitter	clinical testing	Institute of Human Genetics, University of Leipzig Medical Center	Jun 28, 2023	Criteria applied: PS4,PS3_MOD,PM5,PP3,PP4 -
Pathogenic, reviewed by expert panel	curation	ClinGen Malignant Hyperthermia Susceptibility Variant Curation Expert Panel, ClinGen	Mar 14, 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 threonine with methionine at codon 2206 of the RYR1 protein, p.(Thr2206Met). The maximum allele frequency for this variant among the six major gnomAD populations is EAS: 0.00005, a frequency consistent with pathogenicity for MHS. This variant has been reported in 67 unrelated individuals who have a personal or family history of a malignant hyperthermia reaction, 63 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, 24433488, 23558838, 10484775, 25735680, 25960145, 16163667, 11575529, 12220451, 12434264, 15731587, 17081152, 18505122, 22696611, 9497245, 25268394, 31559918). This variant has been identified in at least three individuals with negative IVCT/CHCT results, BS2 (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 myotubes from two related individuals showed an increased sensitivity to RYR1 agonists (PMID: 12220451). 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). Another variant that has been assessed as pathogenic occurs at this codon, p.(Thr2206Arg), PM5. This variant segregates with MHS in nine individuals, PP1_Strong (PMID: 12059893, 25960145). A REVEL score >0.85 (0.95) 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: PS4, PS3_Moderate, PM1_Supporting, PM5, PP1_Strong, PP3_Moderate, BS2. -
Pathogenic, no assertion criteria provided	clinical testing	Clinical Genetics Laboratory, University Hospital Schleswig-Holstein	Dec 01, 2021	- -

not provided Pathogenic:6 Other:1

not provided, no classification provided	literature only	Leiden Muscular Dystrophy (RYR1)	-	- -
Pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Jul 19, 2022	Identified in the heterozygous state in association with malignant hyperthermia in published literature (Manning et al., 1998; Monnier et al., 2005; Ibarra et al., 2019); Identified in the heterozygous state in two siblings with myalgia and suspected rhabdomyolysis in published literature (Witting et al., 2018); Published functional studies demonstrate enhanced sensitivity to caffeine and 4-chloro-m-cresol (Wehner et al., 2002; Murayama et al., 2016); Not observed at a significant frequency in large population cohorts (gnomAD); In silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect; This variant is associated with the following publications: (PMID: 15448513, 27586648, 30236257, 19648156, 18505122, 11575529, 12059893, 12208234, 23558838, 16917943, 18564801, 25558065, 32552793, 32665702, 33087929, 9497245, 16163667, 31206373, 23919265, 29635721, 12220451, 30611313, 31127727, 32528171, 32419263, 31321302, 19919814, 12668474) -
Pathogenic, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Sep 03, 2021	The RYR1 c.6617C>T; p.Thr2206Met variant (rs118192177) is reported in the literature in several individuals affected with malignant hyperthermia and segregates with disease in families (selected references: Brandom 2013, Manning 1998, Wehner 2002). Results of caffeine challenge in patients and in vitro assessment of calcium homeostasis are consistent with malignant hyperthermia (Murayama 2016, Wehner 2002). The variant is reported as pathogenic by several sources in the ClinVar database (Variation ID: 12977) and is listed in the general population with an overall allele frequency of 0.002% (6/282,614 alleles) in the Genome Aggregation Database. The threonine at codon 2206 is highly conserved and computational analyses predict that this variant is deleterious (REVEL: 0.95). Based on available information, this variant is considered to be pathogenic. References: Brandom BW et al. Ryanodine receptor type 1 gene variants in the malignant hyperthermia-susceptible population of the United States. Anesth Analg. 2013 May;116(5):1078-86. PMID: 23558838. Manning BM et al. Identification of novel mutations in the ryanodine-receptor gene (RYR1) in malignant hyperthermia: genotype-phenotype correlation. Am J Hum Genet. 1998 Mar;62(3):599-609. PMID: 9497245. Murayama T et al. Genotype-Phenotype Correlations of Malignant Hyperthermia and Central Core Disease Mutations in the Central Region of the RYR1 Channel. Hum Mutat. 2016 Nov;37(11):1231-1241. PMID: 27586648. Wehner M et al. Increased sensitivity to 4-chloro-m-cresol and caffeine in primary myotubes from malignant hyperthermia susceptible individuals carrying the ryanodine receptor 1 Thr2206Met (C6617T) mutation. Clin Genet. 2002 Aug;62(2):135-46. PMID: 12220451. -
Pathogenic, criteria provided, single submitter	clinical testing	Revvity Omics, Revvity	Sep 25, 2023	- -
Pathogenic, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	Jan 08, 2018	- -
Pathogenic, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Nov 01, 2023	RYR1: PP1:Strong, PM5, PS4:Moderate, PP3, PS3:Supporting -
Pathogenic, criteria provided, single submitter	clinical testing	Genetic Services Laboratory, University of Chicago	Nov 23, 2015	- -

Malignant hyperthermia of anesthesia Pathogenic:2

Pathogenic, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	May 05, 2020	Variant summary: RYR1 c.6617C>T (p.Thr2206Met) results in a non-conservative amino acid change located in the RIH domain (IPR000699) of 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 2e-05 in 251224 control chromosomes (gnomAD). c.6617C>T has been reported in the literature in numerous individuals affected with Malignant Hyperthermia Susceptibility and was also shown to co-segregate with disease in families (e.g. Manning_1998, Carpenter_2009, Brandom_2013, Klinger_2014). Functional studies have shown the variant to disrupt cellular calcium homeostasis (e.g. Wehner_2002). Five clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All laboratories classified the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic. -
Pathogenic, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Feb 19, 2021	The p.Thr2206Met variant in RYR1 has been reported in the heterozygous state in >30 individuals with malignant hyperthermia (MH) and segregated with disease in 6 relatives from 3 families (Manning 1998 PMID: 9497245, Rueffert 2002 PMID: 19919814, Carpenter 2009 PMID: 19648156, Sambuughin 2001 PMID: 11575529, Wehner 2002 PMID: 12220451, Alazami 2015 PMID: 25558065, Miller 2018 PMID: 30236257, Ibarra Moreno 2019 PMID: 31206373). It was also reported in the heterozygous state in at least 1 individual with multi-minicore myopathy and in the homozygous state in 1 individual with muscular dystrophy (Amburgey 2013 PMID: 23919265). Additionally, it has been reported by other clinical laboratories in ClinVar (Variation ID: 12977) and has been identified in 0.004% (5/129110) of European chromosomes and 0.005% (1/19446) of East Asian by gnomAD (http://gnomad.broadinstitute.org). In vitro functional studies provide some evidence that the p.Thr2206Met variant may impact RYR1 protein function (Wehner 2002 PMID: 12220451, Murayama 2016 PMID: 27586648), and computational prediction tools and conservation analysis suggest that this variant may impact the protein. This variant lies in the central region of the protein and missense variants in this region are statistically more likely to be disease-associated (Maclennan 2011 PMID: 21118704). In summary, this variant meets criteria to be classified as pathogenic for MH in an autosomal dominant manner. ACMG/AMP Criteria applied: PS4, PM1, PP1_Moderate, PM2_Supporting, PP3, PS3_Supporting. -

Malignant hyperthermia, susceptibility to Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Human Genome Sequencing Center Clinical Lab, Baylor College of Medicine

Jun 13, 2019

The c.6617C>T (p.Thr2206Met) variant in the RYR1 gene, that encodes ryanodine receptor 1, has been identified in numerous unrelated individuals (>50) with personal or family history of a malignant hyperthermia reaction and a positive in-vitro contracture test (IVCT) or caffeine halothane contracture test (CHCT) result (PMID: 30236257, 12059893, 24433488, 23558838, 10484775, 25735680, 25960145, 16163667, 11575529, 12220451, 12434264, 15731587, 17081152, 18505122, 22696611, 9497245, 25268394, 31559918, ClinGen Review [ClinVar ID:12977]). This variant segregates with malignant hyperthermia syndrome (MHS) in nine individuals (PMID: 12059893, 25960145).This missense variant resides in a mutational hot spot region that contributes to MHS (PMID: 21118704). A functional study in HEK293 cells shows an increased sensitivity to RYR1 agonists (PMID: 27586648). In-silico computational prediction tools suggest that the p.Thr2206Met variant may have deleterious effect on the protein function (REVEL score: 0.95). This variant has been interpreted as pathogenic by several submitters in ClinVar database including the ClinGen expert panel (ClinVar ID: 12977). Therefore, the c.6617C>T (p.Thr2206Met) variant in the RYR1 gene is classified as pathogenic. -

RYR1-related disorder Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Invitae

Jan 21, 2024

This sequence change replaces threonine, which is neutral and polar, with methionine, which is neutral and non-polar, at codon 2206 of the RYR1 protein (p.Thr2206Met). This variant is present in population databases (rs118192177, gnomAD 0.003%). This missense change has been observed in individual(s) with malignant hyperthermia susceptibility and/or RYR1-related myopathy (PMID: 9497245, 12220451, 16835904, 19648156, 19919814, 23558838, 23919265, 24433488, 25960145; Invitae). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 12977). 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: 12220451, 16084090, 27586648). For these reasons, this variant has been classified as Pathogenic. -

Ptosis;C0344490:Absence of the sacrum;CN228299:History of neonatal hypotonia Pathogenic:1

Likely pathogenic, no assertion criteria provided

research

Center for Genomic Medicine, King Faisal Specialist Hospital and Research Center

Dec 01, 2014

- -

King Denborough syndrome Pathogenic:1

Pathogenic, no assertion criteria provided

literature only

OMIM

Aug 01, 2002

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.75
BayesDel_addAF	Pathogenic	0.46	D
BayesDel_noAF	Pathogenic	0.49
CADD	Uncertain	25
DANN	Uncertain	1.0
Eigen	Pathogenic	0.71
Eigen_PC	Uncertain	0.66
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Pathogenic	1.0	D;D
M_CAP	Pathogenic	0.66	D
MetaRNN	Pathogenic	0.95	D;D
MetaSVM	Pathogenic	1.0	D
MutationAssessor	Uncertain	2.5	M;M
MutationTaster	Benign	1.0	D;D;D
PrimateAI	Pathogenic	0.90	D
PROVEAN	Pathogenic	-5.2	D;D
REVEL	Pathogenic	0.95
Sift	Pathogenic	0.0	D;D
Polyphen		1.0	D;D
Vest4		0.90
MVP		1.0
MPC		0.32
ClinPred		0.98	D
GERP RS		4.6
Varity_R		0.72
gMVP		0.87

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: rs118192177; hg19: chr19-38986923;