NM_000540.3:c.32A>C

Variant names:

• chr19-38433861-A-C
• NM_000540.3:c.32A>C
• RYR1 p.Gln11Pro

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 (ACMG Germline Pathogenicity v2019). PM2PP3_Moderate

The NM_000540.3(RYR1):c.32A>C (p.Gln11Pro) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant is absent from the gnomAD population database at sites with sufficient sequencing coverage. In-silico predictor (REVEL) classifies this variant as likely damaging/oncogenic. Splicing prediction tools (SpliceAI) predict no significant impact on normal splicing. Variant has been reported in ClinVar as Uncertain Significance (★). Other variants at the same amino acid position have been reported in ClinVar (not pathogenic): p.Q11?: Uncertain_significance (ClinVar VariationId 3387614, 1 star); p.Q11H: Uncertain_significance (ClinVar VariationId 3900387, 1 star); p.Q11= (synonymous): Likely_benign (ClinVar VariationId 763357, 1 star)

• Frequency: Genomes: not found (cov: 30)
• Consequence: RYR1 NM_000540.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 4.88
• 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 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: Uncertain_significance. The variant received 4 points.

Apply	Criterion Code & Title / Strength	Strength	Rationale / Clinical Context
	PM2Absent/extremely low in population databases		Absent from gnomAD (AD/XL gene) — PM2; Absent from gnomAD at well-covered site (MOI: AD+AR) (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 — moderate evidence (PP3); Splicing verdict: not pathogenic.; Germline computational verdict: pathogenic (Moderate).

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.32A>C p.Gln11Pro	missense	Exon 1 of 106	Prot: NP_000531.2 UniProt:
	RYR1 NM_001042723.2		c.32A>C p.Gln11Pro	missense	Exon 1 of 105	Prot: NP_001036188.1 UniProt:

RYR1 NM_000540.3

MANE Select

HGVSc / HGVSpc.32A>Cp.Gln11Pro

Exon rankExon 1 of 106

missense

Prot: NP_000531.2UniProt: P21817-1

RYR1 NM_001042723.2

HGVSc / HGVSpc.32A>Cp.Gln11Pro

Exon rankExon 1 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.32A>C p.Gln11Pro	missense	Exon 1 of 106	Prot: ENSP00000352608.2 UniProt:
	RYR1 ENST00000355481.8	TSL:1	c.32A>C p.Gln11Pro	missense	Exon 1 of 105	Prot: ENSP00000347667.3 UniProt:
	RYR1 ENST00000594335.6	TSL:1	n.32A>C	non_coding_transcript_exon	Exon 1 of 103	Prot: ENSP00000470927.2 UniProt:

RYR1 ENST00000359596.8

TSL:5MANE Select

HGVSc / HGVSpc.32A>Cp.Gln11Pro

Exon rankExon 1 of 106

missense

Prot: ENSP00000352608.2UniProt: P21817-1

RYR1 ENST00000355481.8

TSL:1

HGVSc / HGVSpc.32A>Cp.Gln11Pro

Exon rankExon 1 of 105

missense

Prot: ENSP00000347667.3UniProt: P21817-2

RYR1 ENST00000594335.6

TSL:1

HGVSc / HGVSpn.32A>C

Exon rankExon 1 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 4 sources Large-scale international reference populations
GnomAD3 genomes	AF:	AC:	Hom:	AN:	Cov:30
GnomAD4 exome	AF:	AC:	Hom:	AN:	Cov:32
GnomAD4 genome	AF:	AC:	Hom:	AN:	Cov:30
ALFA (dbGaP/dbSNP Allele Frequency Aggregator)	AF: 0.0000611	AC:1	Hom:0	AN:16362	Cov:

Showing 4 sources

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	Malignant hyperthermia, susceptibility to, 1 (1)

Computational Scores

Algorithm	Calibrated pred.	Score	Prediction
AlphaGenome AVI	Pathogenic	23
AlphaMissense	Benign	0.26
BayesDel_addAF	Pathogenic	0.36	D
BayesDel_noAF	Pathogenic	0.27
CADD	Uncertain	25
DANN	Uncertain	0.98
DEOGEN2	Pathogenic	0.82	D
Eigen	Uncertain	0.56
Eigen_PC	Uncertain	0.55
FATHMM_MKL	Uncertain	0.86	D
FuncVEP CTI	Pathogenic	0.74
GPN-Star LLR	N/A	-8.4
GPN-Star score	N/A	8.4
LIST_S2	Uncertain	0.93	D
M_CAP	Uncertain	0.23	D
MetaRNN	Pathogenic	0.89	D
MetaSVM	Pathogenic	1.1	D
Mutation Taster	N/A	48/52	disease causing
MutationAssessor	Uncertain	2.2	M
PhyloP100	Uncertain	4.9
PrimateAI	Uncertain	0.67	T
PromoterAI	N/A	-0.084	Neutral
PROVEAN	Uncertain	-3.2	D
REVEL	Pathogenic	0.83
Sift	Benign	0.044	D
Varity_R	N/A	0.69
VESM-3B	Benign	-6.8

Showing 27 of 27 scores

Splicing Scores

Algorithm	Calibrated pred.	Score	Prediction
Pangolin (max)	Benign	0.020
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

hg19: chr19-38924501;

ACMG debug oncogenicity

ACGS debug oncogenicity

ACMG debug germline

Submit to ClinVar