chr19-38485988-C-A

Variant names:

• chr19-38485988-C-A
• rs367543055
• NM_000540.3:c.5333C>A
• RYR1 p.Ser1778*

GermlineCancer (beta)

Variant summary

Our verdict is Pathogenic.

+12 Pathogenic

-7

-6

-1

0

+5

+6

+9

+10

BenignB

Likely BenignLB

UncertainVUS

Likely PathogenicLP

PathogenicP

The variant received 12 classification points (ACMG Germline Pathogenicity v2019). PVS1PM2PP5_Moderate

The NM_000540.3(RYR1):c.5333C>A (p.Ser1778*) variant causes a stop gained change involving the alteration of a non-conserved nucleotide. The variant is predicted to lead to nonsense-mediated mRNA decay (NMD). The variant allele was found at a cumulative frequency of 0.00000411 (AC=6) in the gnomAD database across 1,461,290 control chromosomes (no homozygotes observed). The grpmax filtering allele frequency (95% CI) is 0.00000194. In-silico predictor (BayesDel (noAF)) 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 Pathogenic/Likely Pathogenic (★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000041 (0 hom.)
• Consequence: RYR1 NM_000540.3 stop_gained
• Clinical Significance: Pathogenic criteria provided, single submitter P:1 O:1
• Conservation: PhyloP100: 4.99
• Publications: 2 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 12 points.

Apply	Criterion Code & Title / Strength	Strength	Rationale / Clinical Context
	PVS1Null variant in LOF gene		Frameshift/stop-gained, NMD predicted, LoF disease mechanism — very strong (PVS1); Stop-gained (exon 34 of 106) at amino acid 1778 of 5038, predicted to trigger nonsense-mediated mRNA decay. Loss of function is a known disease mechanism for this gene.
	PM2Absent/extremely low in population databases		Very rare in gnomAD for AD/XL gene (popmax AF < threshold/10) — PM2; GnomAD popmax AF = 0.00000194 — very rare for AD+AR gene (base 0.0001, raised to 0.000212 by highest known P/LP ClinVar AF 0.000212) — PM2 moderate.
	PP5Reputable source reports pathogenic		ClinVar 1-star pathogenic — moderate (PP5); ClinVar germline classification: Pathogenic/Likely Pathogenic, 1 star(s).

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.5333C>A p.Ser1778*	stop_gained	Exon 34 of 106	Prot: NP_000531.2 UniProt:
	RYR1 NM_001042723.2		c.5333C>A p.Ser1778*	stop_gained	Exon 34 of 105	Prot: NP_001036188.1 UniProt:

RYR1 NM_000540.3

MANE Select

HGVSc / HGVSpc.5333C>Ap.Ser1778*

Exon rankExon 34 of 106

stop_gained

Prot: NP_000531.2UniProt: P21817-1

RYR1 NM_001042723.2

HGVSc / HGVSpc.5333C>Ap.Ser1778*

Exon rankExon 34 of 105

stop_gained

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.5333C>A p.Ser1778*	stop_gained	Exon 34 of 106	Prot: ENSP00000352608.2 UniProt:
	RYR1 ENST00000355481.8	TSL:1	c.5333C>A p.Ser1778*	stop_gained	Exon 34 of 105	Prot: ENSP00000347667.3 UniProt:
	RYR1 ENST00000594335.6	TSL:1	n.5333C>A	non_coding_transcript_exon	Exon 34 of 103	Prot: ENSP00000470927.2 UniProt:

RYR1 ENST00000359596.8

TSL:5MANE Select

HGVSc / HGVSpc.5333C>Ap.Ser1778*

Exon rankExon 34 of 106

stop_gained

Prot: ENSP00000352608.2UniProt: P21817-1

RYR1 ENST00000355481.8

TSL:1

HGVSc / HGVSpc.5333C>Ap.Ser1778*

Exon rankExon 34 of 105

stop_gained

Prot: ENSP00000347667.3UniProt: P21817-2

RYR1 ENST00000594335.6

TSL:1

HGVSc / HGVSpn.5333C>A

Exon rankExon 34 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:32
GnomAD4 exome	AF: 0.00000411	AC:6	Hom:0	AN:1461290	Cov:33
GnomAD4 genome	AF:	AC:	Hom:	AN:	Cov:32
ALFA (dbGaP/dbSNP Allele Frequency Aggregator)	AF: 0.0000539	AC:2	Hom:0	AN:37124	Cov:

Showing 4 sources

ClinVar

ClinVar submissions

Significance: Pathogenic

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
1	-	-	RYR1-related disorder (1)
-	-	-	Congenital myopathy with fiber type disproportion (1)

Computational Scores

Algorithm	Calibrated pred.	Score	Prediction
AlphaGenome AVI	Pathogenic	34
BayesDel_addAF	Pathogenic	0.57	D
BayesDel_noAF	Pathogenic	0.59
CADD	Pathogenic	38
DANN	Uncertain	0.99
Eigen	Uncertain	0.30
Eigen_PC	Benign	0.0070
FATHMM_MKL	Pathogenic	0.98	D
GPN-Star LLR	N/A	-8.4
GPN-Star score	N/A	8.4
Mutation Taster	N/A	1/199	disease causing (ClinVar)
PhyloP100	Uncertain	5.0

Showing 12 of 12 scores

Splicing Scores

Algorithm	Calibrated pred.	Score	Prediction
Pangolin (max)	Benign	0.030
SpliceAI score (max)	Benign	0.010	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: rs367543055;

hg19: chr19-38976628;

ACMG debug oncogenicity

ACGS debug oncogenicity

ACMG debug germline

Submit to ClinVar