19-38523211-C-G

Variant names:

Variant summary

Our verdict is Pathogenic. The variant received 5 ACMG points: 5P and 0B. PP4PP1PM3PS3_Supporting

This summary comes from the ClinGen Evidence Repository: The variant NM_000540.3(RYR1):c.10348-6C>G in RYR1 is an intronic variant located in intron 68. The filtering allele frequency is 0.0003329 (34/75078 alleles, 0 homozygotes) for the African/African American population, which meets no codes. In addition, the SpliceAI Acceptor Loss value is 0.47. The variant was found in compound heterozygosity with variants of uncertain significance, likely pathogenic, or pathogenic variants in 22 patients (PM3_Very Strong; PMIDs: 18253926, 21062345, 20839240, 23553484, 28818389, 30932294, 31069529, 30611313, 34440373, 35627144, 35616356, 36939041). At least 3 patients with this variant displayed ophthalmoparesis and presence of cores on muscle biopsy, which is highly specific for RYR1-related myopathy (PP4; PMID:20839240). This variant has been observed in at least 11 South African patients with RYR1-related myopathy, suggesting a possible founder variant (PMID:20839240). The variant has also been reported in cis with the c.14524G>A (p.Val4842Met) variant in 17 of the 22 probands, which is part of a known haplotype and has been reported as a compound heterozygous change in individuals with RYR1-related myopathies (PMIDs: 18253926, 21062345, 20839240, 23553484, 30932294, 30611313, 35627144). The variant has been found to segregate with disease in 4 affected relatives from 2 families (PP1; PMIDs: 18253926, 21062345). Functional studies in patient cells showed that the variant resulted in a loss of splicing of intron 68 and the introduction of a premature stop codon causing the mRNA to undergo NMD (PMIDs: 18253926, 25525159) (PS3_Supporting). In summary, this variant meets the criteria to be classified as pathogenic for autosomal recessive RYR1-related myopathy based on the ACMG/AMP criteria applied, as specified by the ClinGen Congenital Myopathies VCEP: PM3_Very Strong, PP4, PP1, PS3_Supporting (ClinGen Congenital Myopathies VCEP specifications version 2; May 19th, 2025). LINK:https://erepo.genome.network/evrepo/ui/classification/CA023836/MONDO:0100150/179

Frequency

Genomes: 𝑓 0.000085 ( 0 hom., cov: 31)

Exomes 𝑓: 0.000021 ( 0 hom. )

Consequence

RYR1
NM_000540.3 splice_region, intron

Scores

Splicing: ADA: 0.0001551

Clinical Significance

Pathogenic reviewed by expert panel P:17U:1O:1

Conservation

PhyloP100: -0.101

Publications

7 publications found

Variant links:

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: Labcorp Genetics (formerly Invitae), PanelApp Australia, Genomics England PanelApp, Ambry Genetics, ClinGen
RYR1-related myopathy
Inheritance: AD, AR Classification: DEFINITIVE, STRONG Submitted by: ClinGen, PanelApp Australia
congenital multicore myopathy with external ophthalmoplegia
Inheritance: AR Classification: DEFINITIVE, STRONG Submitted by: G2P, Genomics England PanelApp
central core myopathy
Inheritance: AD, AR Classification: STRONG, SUPPORTIVE Submitted by: Orphanet, Labcorp Genetics (formerly Invitae), Genomics England PanelApp
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

RYR1 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Pathogenic. The variant received 5 ACMG points.

PS3

For more information check the summary or visit ClinGen Evidence Repository.

PM3

For more information check the summary or visit ClinGen Evidence Repository.

PP1

For more information check the summary or visit ClinGen Evidence Repository.

PP4

For more information check the summary or visit ClinGen Evidence Repository.

Variant Effect in Transcripts

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

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	RYR1	NM_000540.3	MANE Select	c.10348-6C>G		splice_region intron	N/A	NP_000531.2	P21817-1
	RYR1	NM_001042723.2		c.10348-6C>G		splice_region intron	N/A	NP_001036188.1	P21817-2

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	Effect	Exon Rank	Protein	UniProt
RYR1	ENST00000359596.8	TSL:5 MANE Select	c.10348-6C>G	splice_region intron	N/A	ENSP00000352608.2	P21817-1
RYR1	ENST00000355481.8	TSL:1	c.10348-6C>G	splice_region intron	N/A	ENSP00000347667.3	P21817-2
RYR1	ENST00000594335.6	TSL:1	n.*1091-6C>G	splice_region intron	N/A	ENSP00000470927.2	M0R014

Frequencies

GnomAD3 genomes

AF:

0.0000854

AC:

AN:

152242

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000313

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:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.0000199

AC:

AN:

251458

AF XY:

0.0000147

show subpopulations

Gnomad AFR exome

AF:

0.000246

Gnomad AMR exome

AF:

0.0000289

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000205

AC:

AN:

1461888

Hom.:

Cov.:

AF XY:

0.0000165

AC XY:

AN XY:

727244

show subpopulations

African (AFR)

AF:

0.000627

AC:

AN:

33480

American (AMR)

AF:

0.0000224

AC:

AN:

44724

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26136

East Asian (EAS)

AF:

0.00

AC:

AN:

39700

South Asian (SAS)

AF:

0.00

AC:

AN:

86258

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53420

Middle Eastern (MID)

AF:

0.000173

AC:

AN:

5768

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

1112006

Other (OTH)

AF:

0.000116

AC:

AN:

60396

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.457

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.0000853

AC:

AN:

152360

Hom.:

Cov.:

AF XY:

0.000121

AC XY:

AN XY:

74496

show subpopulations

African (AFR)

AF:

0.000313

AC:

AN:

41598

American (AMR)

AF:

0.00

AC:

AN:

15304

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3472

East Asian (EAS)

AF:

0.00

AC:

AN:

5178

South Asian (SAS)

AF:

0.00

AC:

AN:

4832

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10628

Middle Eastern (MID)

AF:

0.00

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

68032

Other (OTH)

AF:

0.00

AC:

AN:

2110

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.513

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.00

Hom.:

Bravo

AF:

0.000113

ClinVar

ClinVar submissions

Significance:Pathogenic

Revision:reviewed by expert panel

View on ClinVar

Pathogenic

VUS

Benign

Condition

not provided (5)

RYR1-related disorder (3)

Central core myopathy (2)

Centronuclear myopathy (1)

Congenital multicore myopathy with external ophthalmoplegia (1)

Inborn genetic diseases (1)

King Denborough syndrome (1)

King Denborough syndrome;C1850674:Congenital multicore myopathy with external ophthalmoplegia;C2930980:Malignant hyperthermia, susceptibility to, 1;C5830701:Central core myopathy (1)

King Denborough syndrome;C1850674:Congenital multicore myopathy with external ophthalmoplegia;C5830701:Central core myopathy (1)

Malignant hyperthermia, susceptibility to, 1 (1)

Myopathy, RYR1-associated (1)

RYR1-related myopathy (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.83

CADD

Benign

7.2

(source)

DANN

Benign

0.66

PhyloP100

-0.10

Mutation Taster

=4/96

disease causing (ClinVar)

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

dbscSNV1_ADA

Benign

0.00016

dbscSNV1_RF

Benign

0.13

SpliceAI score (max)

0.47

Details are displayed if max score is > 0.2

DS_AL_spliceai

0.47

Position offset: 6

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

Publications

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over