RYR1 p.Thr2206Met

Variant names:

• chr19-38496283-C-T
• rs118192177
• NM_000540.3:c.6617C>T
• RYR1 p.Thr2206Met

GermlineCancer (beta)

Variant summary

Our verdict is Pathogenic.

>+14 Pathogenic

-7

-6

-1

0

+5

+6

+9

+10

BenignB

Likely BenignLB

UncertainVUS

Likely PathogenicLP

PathogenicP

The variant received 20 classification points (ACMG Germline Pathogenicity v2019). PS3PM1PM2PP3_StrongPP5_Very_Strong

The NM_000540.3(RYR1):c.6617C>T (p.Thr2206Met) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a cumulative frequency of 0.0000223 (AC=36) in the gnomAD database across 1,613,882 control chromosomes (no homozygotes observed). The grpmax filtering allele frequency (95% CI) is 0.0000197. In-silico predictor (REVEL) classifies this variant as likely damaging/oncogenic. Splicing prediction tools (SpliceAI) predict no significant impact on normal splicing. The affected nucleotide is highly conserved across species (PhyloP 100-way vertebrate score: 7.91). Variant has been reported in ClinVar as Pathogenic/Likely Pathogenic (★★★). ClinVar reports functional evidence for this variant: "SCV001434860: Multiple independent in vitro experiments showed this variant is functionally damaging (PMID 12220451, 19648156, 27586648)." and additional evidence is available in ClinVar. Other variants at the same amino acid position have been reported in ClinVar (not pathogenic): p.T2206R: not_provided (ClinVar VariationId 133164); p.T2206= (synonymous): Likely_benign (ClinVar VariationId 2144678, 2 stars) This exact variant is curated in the UniProt human variants database as Pathogenic, associated with Malignant hyperthermia, susceptibility to, 1 (mhs1).

• 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:28 O:2
• Conservation: PhyloP100: 7.91
• Publications: 5 publications found

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 Gene-Disease associations (from GenCC):

• malignant hyperthermia, susceptibility to, 1

  Inheritance: AD Classification: DEFINITIVE, STRONG Submitted by: Ambry Genetics, PanelApp Australia, Labcorp Genetics (formerly Invitae), Genomics England PanelApp, ClinGen
• RYR1-related myopathy

  Inheritance: AD, AR Classification: DEFINITIVE, STRONG Submitted by: PanelApp Australia, ClinGen
• congenital multicore myopathy with external ophthalmoplegia

  Inheritance: AR Classification: DEFINITIVE, STRONG Submitted by: G2P, Genomics England PanelApp
• central core myopathy

  Inheritance: AR, AD Classification: STRONG, SUPPORTIVE Submitted by: Genomics England PanelApp, Orphanet, Labcorp Genetics (formerly Invitae)
• King-Denborough syndrome

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• malignant hyperthermia of anesthesia

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• autosomal recessive centronuclear myopathy

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet
• benign Samaritan congenital myopathy

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet
• congenital myopathy with myasthenic-like onset

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet
• lethal multiple pterygium syndrome

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

Classification according to ACMG Germline Pathogenicity v2019

Specifications for RYR1 are available in the ClinGen Criteria Specification Registry and recommended for reference when assigning criteria.

Classification was made for transcript:

Our verdict: Pathogenic. The variant received 20 points.

Apply	Criterion Code & Title / Strength	Strength	Rationale / Clinical Context
	PS3Functional studies show damaging effect		Well-established functional study supports damaging effect (PS3); SCV001434860: Multiple independent in vitro experiments showed this variant is functionally damaging (PMID 12220451, 19648156, 27586648).; SCV002318979: 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).; SCV004358102: "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)."; SCV004820887: A functional study in HEK293 cells shows an increased sensitivity to RYR1 agonists (PMID: 27586648).; SCV005399216: "In vitro studies demonstrated increased sensitivity to 4-chloro-m-cresol and caffeine (PMID: 12220451)."; SCV006555760: "In support of this prediction, functional studies in a cell culture model show an increased sensitivity to RYR1 agonists and patient-derived myotubes from two related individuals showed an increased sensitivity to RYR1 agonists (Murayama T et al., PMID: 27586648; Wehner M et al., PMID: 12220451)."; SCV000581797: Published functional studies demonstrate enhanced sensitivity to caffeine and 4-chloro-m-cresol (Wehner et al., 2002; Murayama et al., 2016); SCV002047761: Results of caffeine challenge in patients and in vitro assessment of calcium homeostasis are consistent with malignant hyperthermia (Murayama 2016, Wehner 2002). PMID: 27586648, PMID: 12220451; SCV000712440: "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)"; SCV001370553: Functional studies have shown the variant to disrupt cellular calcium homeostasis (e.g. Wehner_2002).; SCV000777489: Experimental studies have shown that this missense change affects RYR1 function (PMID: 12220451, 16084090, 27586648).; SCV005045776: A functional study in HEK293 cells shows an increased sensitivity to RYR1 agonists (PMID: 27586648).; SCV005161789: positive in vitro contracture test (IVCT) and/or a reported malignant hyperthermia event (Manning, 1998; Wang, 2008; Brandom, 2013; Klingler, 2014; Wehner, 2002).
	PM1Mutational hot spot or critical domain		Missense neighbourhood hotspot (≥2 P/LP within ±8 AA, OR ≥ 5 vs. background) — PM1; In-domain: 0 pathogenic, 0 benign rare missense variants.; ±8 AA neighbourhood: 5 pathogenic, 0 benign (OR vs. background: 55.0).
	PM2Absent/extremely low in population databases		Very rare in gnomAD for AD/XL gene (popmax AF < threshold/10) — PM2; GnomAD popmax AF = 0.0000197 — very rare for AD+AR gene (base 0.0001, raised to 0.000212 by highest known P/LP ClinVar AF 0.000212) — PM2 moderate.
	PP3Computational evidence supports damaging effect		Germline meta computational scorer (REVEL/MetaRNN/BayesDel) predicts damaging effect — strong evidence (PP3); Splicing verdict: not pathogenic.; Germline computational verdict: pathogenic (Strong).
	PP5Reputable source reports pathogenic		ClinVar ≥3 stars pathogenic — very strong (PP5); ClinVar submissions overwhelmingly pathogenic (≥10 total, ≥80% P/LP, <10% B/LB) — strong (PP5, count-based); ClinVar germline classification: Pathogenic/Likely Pathogenic, 3 star(s). ClinVar submissions strongly and reliably favor pathogenicity (28/28 total P/LP).

Variant Effect in Transcripts

Automated classification analysis was done for transcript: NM_000540.3. You can select a different transcript below to see updated classification assignments.

RefSeq Transcripts

Sel.	Gene / Transcript	Tags	HGVSc / HGVSp	Effect	Exon rank	Protein / UniProt
	RYR1 NM_000540.3	MANE Select	c.6617C>T p.Thr2206Met	missense	Exon 40 of 106	Prot: NP_000531.2 UniProt:
	RYR1 NM_001042723.2		c.6617C>T p.Thr2206Met	missense	Exon 40 of 105	Prot: NP_001036188.1 UniProt:

RYR1 NM_000540.3

MANE Select

HGVSc / HGVSpc.6617C>Tp.Thr2206Met

Exon rankExon 40 of 106

missense

Prot: NP_000531.2UniProt: P21817-1

RYR1 NM_001042723.2

HGVSc / HGVSpc.6617C>Tp.Thr2206Met

Exon rankExon 40 of 105

missense

Prot: NP_001036188.1UniProt: P21817-2

Ensembl Transcripts

Sel.	Gene / Transcript	Tags	HGVSc / HGVSp	Effect	Exon rank	Protein / UniProt
	RYR1 ENST00000359596.8	TSL:5MANE Select	c.6617C>T p.Thr2206Met	missense	Exon 40 of 106	Prot: ENSP00000352608.2 UniProt:
	RYR1 ENST00000355481.8	TSL:1	c.6617C>T p.Thr2206Met	missense	Exon 40 of 105	Prot: ENSP00000347667.3 UniProt:
	RYR1 ENST00000594335.6	TSL:1	n.6617C>T	non_coding_transcript_exon	Exon 40 of 103	Prot: ENSP00000470927.2 UniProt:

RYR1 ENST00000359596.8

TSL:5MANE Select

HGVSc / HGVSpc.6617C>Tp.Thr2206Met

Exon rankExon 40 of 106

missense

Prot: ENSP00000352608.2UniProt: P21817-1

RYR1 ENST00000355481.8

TSL:1

HGVSc / HGVSpc.6617C>Tp.Thr2206Met

Exon rankExon 40 of 105

missense

Prot: ENSP00000347667.3UniProt: P21817-2

RYR1 ENST00000594335.6

TSL:1

HGVSc / HGVSpn.6617C>T

Exon rankExon 40 of 103

non_coding_transcript_exon

Prot: ENSP00000470927.2UniProt: M0R014

Frequencies

Allele frequencies (AF), counts (AC/AN), homozygotes and coverage

Common (AF > 0.05 / Hom > 5)

Rare (AF ≤ 0.0001 / Hom ≤ 1)

Source / population	AF	AC	Hom	AN	Coverage
Global population databases 6 sources Large-scale international reference populations
GnomAD3 genomes	AF: 0.0000394	AC:6	Hom:0	AN:152168	Cov:32
GnomAD2 exomes	AF: 0.0000199	AC:5	Hom:	AN:251224	Cov:
GnomAD4 exome	AF: 0.0000205	AC:30	Hom:0	AN:1461714	Cov:32
GnomAD4 genome	AF: 0.0000394	AC:6	Hom:0	AN:152168	Cov:32
TOPMed (Bravo)	AF: 0.0000302	AC:	Hom:	AN:	Cov:
ALFA (dbGaP/dbSNP Allele Frequency Aggregator)	AF: 0.0000464	AC:4	Hom:0	AN:86150	Cov:
Local & regional cohorts 2 sources Population-specific and national genomic databases
ChinaMAP Phase 1	AF: 0.0000492	AC:	Hom:	AN:	Cov:
ToMMo 61KJPN (+60KJPN MNV)	AF: 0.00000800	AC:1	Hom:0	AN:122320	Cov:

Showing 8 sources

Case/control cohorts

Cohort	Cases			Controls
	AF	AC	AN	AF	AC	AN
ASC(Autism)	0.000104 *	1	9620	0.00 *	0	10426
BipEx(Bipolar disorder (including schizoaffective))	0.0000352	1	28420	0.0000347	1	28844
Epi25(Epilepsy)	0.00	0	41956	0.0000299	2	66886
SCHEMA(Schizophrenia)	0.0000412	4	97204	0.0000191	3	156662

Showing 4 cohortsAllele count / allele number. AF is computed from the counts for ASC (not provided by the source).

ClinVar

ClinVar submissions

Significance: Pathogenic

Revision: reviewed by expert panel

Pathogenic	VUS	Benign	Condition
13	-	-	Malignant hyperthermia, susceptibility to, 1 (14)
6	-	-	not provided (7)
2	-	-	Malignant hyperthermia of anesthesia (2)
1	-	-	Inborn genetic diseases (1)
1	-	-	King Denborough syndrome (1)
1	-	-	King Denborough syndrome;C1850674:Congenital multicore myopathy with external ophthalmoplegia;C2930980:Malignant hyperthermia, susceptibility to, 1;C5830701:Central core myopathy (1)
1	-	-	King Denborough syndrome;C5830701:Central core myopathy (1)
1	-	-	Malignant hyperthermia, susceptibility to (1)
1	-	-	Ptosis;C0344490:Absence of the sacrum;na:History of neonatal hypotonia (1)
1	-	-	RYR1-related disorder (1)

Computational Scores

Algorithm	Calibrated pred.	Score	Prediction
AlphaGenome AVI	Pathogenic	26
AlphaMissense	Pathogenic	0.75
BayesDel_addAF	Pathogenic	0.46	D
BayesDel_noAF	Pathogenic	0.49
CADD	Uncertain	25
DANN	Uncertain	1.0
DEOGEN2	Pathogenic	0.94	D
Eigen	Pathogenic	0.71
Eigen_PC	Uncertain	0.66
FATHMM_MKL	Pathogenic	0.98	D
GPN-Star LLR	N/A	-8.6
GPN-Star score	N/A	8.6
LIST_S2	Pathogenic	1.0	D
M_CAP	Pathogenic	0.66	D
MetaRNN	Pathogenic	0.95	D
MetaSVM	Pathogenic	1.0	D
Mutation Taster	N/A	0/100	disease causing (ClinVar)
MutationAssessor	Uncertain	2.5	M
PhyloP100	Pathogenic	7.9
PrimateAI	Pathogenic	0.90	D
PROVEAN	Pathogenic	-5.2	D
REVEL	Pathogenic	0.95
Sift	Pathogenic	0.0	D
Varity_R	N/A	0.72
VESM-3B	Benign	-9.4

Showing 25 of 25 scores

Splicing Scores

Algorithm	Calibrated pred.	Score	Prediction
Pangolin (max)	Benign	0.010
SpliceAI score (max)	Benign	0.0	Details are displayed if max score is > 0.2

Showing 2 of 2 scores

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

MaxEntScan Visualizer can be used to analyze the impact of this mutation on the neighboring sequence.

MaveDB functional evidence

MaveDB is a public repository of laboratory assays that test the effect of thousands of variants at once — treat this as supporting research data and interpret it with great caution; it is not a clinical classification.

No MaveDB functional evidence found for this variant.

Other links and lift over

dbSNP: rs118192177;

hg19: chr19-38986923;

ACMG debug oncogenicity

ACGS debug oncogenicity

ACMG debug germline

Submit to ClinVar