NM_000540.3:c.6616_6618delACGinsCGC

Variant names:

• chr19-38496282-ACG-CGC
• NM_000540.3:c.6616_6618delACGinsCGC
• RYR1 p.Thr2206Arg

GermlineCancer (beta)

Variant summary

Our verdict is Uncertain significance.

+4 Uncertain · Hot

-7

-6

-1

0

+5

+6

+9

+10

BenignB

Likely BenignLB

UncertainVUS

Likely PathogenicLP

PathogenicP

The variant received 4 classification points (ACGS-UK Somatic Oncogenicity v2025). O3_ModerateO5_SupportingO7_Supporting

The NM_000540.3(RYR1):c.6616_6618delACGinsCGC (p.Thr2206Arg) variant causes a missense change. The gene RYR1 is a tumor suppressor gene (CancerMine: 1 TSG, 1 oncogene citations). The gene RYR1 is a known oncogene (CancerMine: 1 TSG, 1 oncogene citations). Note: allele frequency estimates from gnomAD may be inaccurate for this variant type (MNP or indel longer than 3 bp) due to technology limitations. The variant is absent from the gnomAD population database at sites with sufficient sequencing coverage. The affected nucleotide is highly conserved across species (PhyloP 100-way vertebrate score: 9.32). No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. A different missense at the same amino acid position has been reported as Pathogenic/Likely Pathogenic in ClinVar: p.T2206M: Pathogenic (ClinVar VariationId 12977, 3 stars) 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: not found (cov: 32)
• Consequence: RYR1 NM_000540.3 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 9.32
• Publications: 0 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 ACGS-UK Somatic Oncogenicity v2025

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: Uncertain_significance. The variant received 4 points.

Apply	Criterion Code & Title / Strength	Strength	Rationale / Clinical Context
	O3Absent or very rare in population		Absent or extremely rare in gnomAD (AC ≤ 2) — O3 moderate; GnomAD: AF = absent, AC = 0 — absent/extremely rare (O3 moderate [+2])
	O5Same location/impact as known oncogenic		Different AA at same residue with oncogenic evidence (or germline P/LP in TSG), or same AA change SCI Tier II Potential — Supporting (O5); ClinVar same-AA oncogenic/T1: false | ClinVar same-AA SCI tier: — | CGI same-AA oncogenic: false | TSG: true | ClinVar same-AA germline P/LP: false | CIViC LOF: false | ClinVar diff-AA oncogenic: false | ClinVar diff-AA germline P/LP: true
	O7Mutational hotspot or critical domain		Supporting: cancerhotspots.org hit, critical domain, or missense neighbourhood hotspot; No cancerhotspots.org hit at this position; UniProt domain: 0 pathogenic, 0 benign.; ±8 AA neighbourhood: 5 pathogenic, 0 benign (OR vs. background: 55.0); Variant does not impact splicing — splice-hotspot path not applicable

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.6616_6618delACGinsCGC p.Thr2206Arg	missense	N/A	Prot: NP_000531.2 UniProt:
	RYR1 NM_001042723.2		c.6616_6618delACGinsCGC p.Thr2206Arg	missense	N/A	Prot: NP_001036188.1 UniProt:

RYR1 NM_000540.3

MANE Select

HGVSc / HGVSpc.6616_6618delACGinsCGCp.Thr2206Arg

Exon rankN/A

missense

Prot: NP_000531.2UniProt: P21817-1

RYR1 NM_001042723.2

HGVSc / HGVSpc.6616_6618delACGinsCGCp.Thr2206Arg

Exon rankN/A

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.6616_6618delACGinsCGC p.Thr2206Arg	missense	N/A	Prot: ENSP00000352608.2 UniProt:
	RYR1 ENST00000355481.8	TSL:1	c.6616_6618delACGinsCGC p.Thr2206Arg	missense	N/A	Prot: ENSP00000347667.3 UniProt:
	RYR1 ENST00000594335.6	TSL:1	n.6616_6618delACGinsCGC	non_coding_transcript_exon	Exon 40 of 103	Prot: ENSP00000470927.2 UniProt:

RYR1 ENST00000359596.8

TSL:5MANE Select

HGVSc / HGVSpc.6616_6618delACGinsCGCp.Thr2206Arg

Exon rankN/A

missense

Prot: ENSP00000352608.2UniProt: P21817-1

RYR1 ENST00000355481.8

TSL:1

HGVSc / HGVSpc.6616_6618delACGinsCGCp.Thr2206Arg

Exon rankN/A

missense

Prot: ENSP00000347667.3UniProt: P21817-2

RYR1 ENST00000594335.6

TSL:1

HGVSc / HGVSpn.6616_6618delACGinsCGC

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 2 sources Large-scale international reference populations
GnomAD3 genomes	AF:	AC:	Hom:	AN:	Cov:32
GnomAD4 genome	AF:	AC:	Hom:	AN:	Cov:32

Showing 2 sources

Tested, but no data found:GnomAD4 exomeIf GnomAD4 is missing, the position is probably not covered by the project.

ClinVar

Not reported in ClinVar

Computational Scores

Algorithm	Calibrated pred.	Score	Prediction
PhyloP100	Pathogenic	9.3

Showing 1 of 1 scores

Splicing Scores

No splicing scores have been computed for this variant.

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

hg19: chr19-38986922;

ACMG debug oncogenicity

ACGS debug oncogenicity

ACMG debug germline

Submit to ClinVar