19-38528963-CAGGAGGAGG-CAGGAGG

Variant names:

Variant summary

Our verdict is Benign. The variant received -10 ACMG points: 0P and 10B. BP3BP6BS1BS2

The NM_000540.3(RYR1):c.11061_11063delGGA(p.Glu3688del) variant causes a disruptive inframe deletion change. The variant allele was found at a frequency of 0.00068 in 1,581,278 control chromosomes in the GnomAD database, including 3 homozygotes. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

Frequency

Genomes: 𝑓 0.0012 ( 0 hom., cov: 32)

Exomes 𝑓: 0.00062 ( 3 hom. )

Consequence

RYR1
NM_000540.3 disruptive_inframe_deletion

Scores

Not classified

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:4B:3

Conservation

PhyloP100: 4.54

Publications

0 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), ClinGen, Genomics England PanelApp, Ambry Genetics
congenital multicore myopathy with external ophthalmoplegia
Inheritance: AR Classification: DEFINITIVE, STRONG Submitted by: G2P, Genomics England PanelApp
RYR1-related myopathy
Inheritance: AR, AD Classification: DEFINITIVE Submitted by: ClinGen
central core myopathy
Inheritance: AD, AR Classification: STRONG, SUPPORTIVE Submitted by: Labcorp Genetics (formerly Invitae), Orphanet, 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: Benign. The variant received -10 ACMG points.

BP3

Nonframeshift variant in repetitive region in NM_000540.3

BP6

Variant 19-38528963-CAGG-C is Benign according to our data. Variant chr19-38528963-CAGG-C is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 218465.We mark this variant Likely_benign, oryginal submission is: [Conflicting_classifications_of_pathogenicity].

BS1

Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.00122 (185/152104) while in subpopulation AFR AF = 0.00248 (103/41538). AF 95% confidence interval is 0.00209. There are 0 homozygotes in GnomAd4. There are 86 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.

BS2

High Homozygotes in GnomAdExome4 at 3 AR,AD gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
RYR1	NM_000540.3 link	c.11061_11063delGGA	p.Glu3688del	disruptive_inframe_deletion	Exon 76 of 106	ENST00000359596.8	NP_000531.2	P21817-1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
RYR1	ENST00000359596.8 link	c.11061_11063delGGA	p.Glu3688del	disruptive_inframe_deletion	Exon 76 of 106	5	NM_000540.3	ENSP00000352608.2		P21817-1

Frequencies

GnomAD3 genomes

AF:

0.00122

AC:

185

AN:

151988

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00249

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000197

Gnomad ASJ

AF:

0.0187

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000177

Gnomad OTH

AF:

0.000957

GnomAD2 exomes

AF:

0.00195

AC:

424

AN:

217000

AF XY:

0.00181

show subpopulations

Gnomad AFR exome

AF:

0.00375

Gnomad AMR exome

AF:

0.000860

Gnomad ASJ exome

AF:

0.0180

Gnomad EAS exome

AF:

0.000663

Gnomad FIN exome

AF:

0.000249

Gnomad NFE exome

AF:

0.00151

Gnomad OTH exome

AF:

0.00239

GnomAD4 exome

AF:

0.000623

AC:

891

AN:

1429174

Hom.:

AF XY:

0.000607

AC XY:

431

AN XY:

710134

show subpopulations

African (AFR)

AF:

0.00314

AC:

103

AN:

32806

American (AMR)

AF:

0.000605

AC:

AN:

42944

Ashkenazi Jewish (ASJ)

AF:

0.0188

AC:

477

AN:

25390

East Asian (EAS)

AF:

0.0000515

AC:

AN:

38802

South Asian (SAS)

AF:

0.000180

AC:

AN:

83194

European-Finnish (FIN)

AF:

0.0000962

AC:

AN:

51996

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5638

European-Non Finnish (NFE)

AF:

0.000148

AC:

161

AN:

1089398

Other (OTH)

AF:

0.00173

AC:

102

AN:

59006

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.452

Heterozygous variant carriers

147

196

245

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

100

<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:

0.00122

AC:

185

AN:

152104

Hom.:

Cov.:

AF XY:

0.00116

AC XY:

AN XY:

74356

show subpopulations

African (AFR)

AF:

0.00248

AC:

103

AN:

41538

American (AMR)

AF:

0.000196

AC:

AN:

15272

Ashkenazi Jewish (ASJ)

AF:

0.0187

AC:

AN:

3470

East Asian (EAS)

AF:

0.00

AC:

AN:

5174

South Asian (SAS)

AF:

0.00

AC:

AN:

4822

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10570

Middle Eastern (MID)

AF:

0.00

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.000177

AC:

AN:

67942

Other (OTH)

AF:

0.000948

AC:

AN:

2110

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.500

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:

0.00719

Hom.:

Bravo

AF:

0.00133

Asia WGS

AF:

0.00289

AC:

AN:

3478

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:4Benign:3

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

Malignant hyperthermia, susceptibility to, 1

Uncertain:1Benign:1

Jul 01, 2013

Biesecker Lab/Clinical Genomics Section, National Institutes of Health

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:research

- -

Mar 28, 2019

Color Diagnostics, LLC DBA Color Health

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

RYR1-related disorder

Uncertain:1Benign:1

Jan 29, 2024

PreventionGenetics, part of Exact Sciences

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

The RYR1 c.11061_11063delGGA variant is predicted to result in an in-frame deletion (p.Glu3689del). This variant has been reported in two individuals with no history of malignant hyperthermia, heat illness, or myopathy (Table S3 - Gonsalves et al. 2013. PubMed ID: 24195946). This variant was also reported in an individual with hypertrophied muscles and persistently elevated serum creatine kinase (Vedanarayanan. American Academy of Neurology 2013 Annual Meeting; https://www.aan.com/MSA/Public/Events/Details/2786). This variant is reported in 1.8% of alleles in individuals of Ashkenazi Jewish descent in gnomAD; however, quality metrics at this site indicate this may not be a reliable estimate of the population frequency. At PreventionGenetics, we have observed this variant in the heterozygous state in ~90 individuals indicating it is likely too common to be a primary cause of an autosomal dominant disorder. Although we suspect this variant is benign, at this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence. -

Jan 30, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

not provided

Uncertain:1Benign:1

Mar 01, 2024

CeGaT Center for Human Genetics Tuebingen

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

RYR1: BS1, BS2 -

May 09, 2023

GeneDx

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Identified as a heterozygous variant in a cohort of African American men with muscle cramps and pain with exertion (Vedanarayanan and Sinclair, 2013); In silico analysis supports a deleterious effect on protein structure/function -

Malignant hypothermia

Uncertain:1

Apr 17, 2015

Genomic Diagnostic Laboratory, Division of Genomic Diagnostics, Children's Hospital of Philadelphia

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

PhyloP100

4.5

Mutation Taster

=17/83

disease causing

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.010

Details are displayed if max score is > 0.2

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

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over