rs780420237

Variant names:

Variant summary

Our verdict is Uncertain significance. The variant received 4 ACMG points: 4P and 0B. PM2PP3_Moderate

The NM_000540.3(RYR1):c.4766A>C(p.Gln1589Pro) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000128 in 1,561,364 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. Q1589K) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.0000066 ( 0 hom., cov: 31)

Exomes 𝑓: 7.1e-7 ( 0 hom. )

Consequence

RYR1
NM_000540.3 missense

Scores

Clinical Significance

Uncertain significance criteria provided, multiple submitters, no conflicts U:6

Conservation

PhyloP100: 9.23

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), 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: Uncertain_significance. The variant received 4 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

PP3

MetaRNN computational evidence supports a deleterious effect, 0.921

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.4766A>C	p.Gln1589Pro	missense	Exon 33 of 106	NP_000531.2	P21817-1
	RYR1	NM_001042723.2		c.4766A>C	p.Gln1589Pro	missense	Exon 33 of 105	NP_001036188.1	P21817-2

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
RYR1	ENST00000359596.8	TSL:5 MANE Select	c.4766A>C	p.Gln1589Pro	missense	Exon 33 of 106	ENSP00000352608.2	P21817-1
RYR1	ENST00000355481.8	TSL:1	c.4766A>C	p.Gln1589Pro	missense	Exon 33 of 105	ENSP00000347667.3	P21817-2
RYR1	ENST00000594335.6	TSL:1	n.4766A>C		non_coding_transcript_exon	Exon 33 of 103	ENSP00000470927.2	M0R014

Frequencies

GnomAD3 genomes

AF:

0.00000657

AC:

AN:

152158

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

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:

0.0000147

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.00000590

AC:

AN:

169454

AF XY:

0.00

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000146

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

7.10e-7

AC:

AN:

1409206

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

696100

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

32302

American (AMR)

AF:

0.00

AC:

AN:

36568

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

25262

East Asian (EAS)

AF:

0.00

AC:

AN:

36966

South Asian (SAS)

AF:

0.00

AC:

AN:

80102

European-Finnish (FIN)

AF:

0.00

AC:

AN:

49414

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5302

European-Non Finnish (NFE)

AF:

9.22e-7

AC:

AN:

1084902

Other (OTH)

AF:

0.00

AC:

AN:

58388

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.525

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

AF:

0.00000657

AC:

AN:

152158

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

74334

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

41430

American (AMR)

AF:

0.00

AC:

AN:

15276

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3470

East Asian (EAS)

AF:

0.00

AC:

AN:

5194

South Asian (SAS)

AF:

0.00

AC:

AN:

4828

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10624

Middle Eastern (MID)

AF:

0.00

AC:

AN:

316

European-Non Finnish (NFE)

AF:

0.0000147

AC:

AN:

68018

Other (OTH)

AF:

0.00

AC:

AN:

2090

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.625

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Alfa

AF:

0.0000508

Hom.:

Bravo

AF:

0.00000756

ExAC

AF:

0.00000847

AC:

ClinVar

ClinVar submissions

Significance:Uncertain significance

Revision:criteria provided, multiple submitters, no conflicts

View on ClinVar

Pathogenic

VUS

Benign

Condition

not provided (2)

Congenital myopathy with fiber type disproportion;C1840365:King Denborough syndrome;C1850674:Congenital multicore myopathy with external ophthalmoplegia;C2930980:Malignant hyperthermia, susceptibility to, 1;C5830701:Central core myopathy (1)

Malignant hyperthermia, susceptibility to, 1 (1)

RYR1-related disorder (1)

RYR1-related myopathy (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.57

BayesDel_addAF

Pathogenic

0.30

BayesDel_noAF

Pathogenic

0.20

CADD

Benign

(source)

DANN

Benign

0.97

DEOGEN2

Pathogenic

0.85

Eigen

Pathogenic

0.81

Eigen_PC

Pathogenic

0.76

FATHMM_MKL

Pathogenic

0.99

LIST_S2

Pathogenic

0.99

M_CAP

Pathogenic

0.79

MetaRNN

Pathogenic

0.92

MetaSVM

Pathogenic

1.1

MutationAssessor

Uncertain

2.8

PhyloP100

9.2

PrimateAI

Benign

0.47

PROVEAN

Pathogenic

-5.5

REVEL

Pathogenic

0.90

Sift

Uncertain

0.0080

Polyphen

1.0

Vest4

0.81

MutPred

0.32

Gain of catalytic residue at Q1589 (P = 0.0026)

MVP

1.0

MPC

1.1

ClinPred

0.95

GERP RS

5.0

Varity_R

0.78

gMVP

0.83

Mutation Taster

=0/100

disease causing

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.0

Details are displayed if max score is > 0.2

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

Publications

You must be logged in to view publications. This limit was set because tens of millions (!) of queries from AI bots are generated daily.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

ClinVar

Computational scores

Splicing

Publications

Other links and lift over