rs193922836

Variant names:

Variant summary

Our verdict is Likely pathogenic. The variant received 6 ACMG points: 6P and 0B. PM2PP3_Strong

The NM_000540.3(RYR1):c.10343C>T(p.Ser3448Phe) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★). Synonymous variant affecting the same amino acid position (i.e. S3448S) has been classified as Likely benign.

Frequency

Genomes: not found (cov: 31)

Consequence

RYR1
NM_000540.3 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter P:1U:1O:1

Conservation

PhyloP100: 7.84

Publications

1 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:

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ACMG classification

Classification was made for transcript

Our verdict: Likely_pathogenic. The variant received 6 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

PP3

MetaRNN computational evidence supports a deleterious effect, 0.963

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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	RYR1	NM_000540.3	MANE Select	c.10343C>T	p.Ser3448Phe	missense	Exon 68 of 106	NP_000531.2
	RYR1	NM_001042723.2		c.10343C>T	p.Ser3448Phe	missense	Exon 68 of 105	NP_001036188.1

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein
RYR1	ENST00000359596.8	TSL:5 MANE Select	c.10343C>T	p.Ser3448Phe	missense	Exon 68 of 106	ENSP00000352608.2
RYR1	ENST00000355481.8	TSL:1	c.10343C>T	p.Ser3448Phe	missense	Exon 68 of 105	ENSP00000347667.3
RYR1	ENST00000594335.6	TSL:1	n.*1086C>T		non_coding_transcript_exon	Exon 67 of 103	ENSP00000470927.2

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

Cov.:

GnomAD4 genome

Cov.:

Alfa

AF:

0.0000258

Hom.:

ClinVar

Significance: Uncertain significance

Submissions summary: Pathogenic:1Uncertain:1Other:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

Congenital multicore myopathy with external ophthalmoplegia

Pathogenic:1

Dec 27, 2005

OMIM

Significance:Pathogenic

Review Status:no assertion criteria provided

Collection Method:literature only

Malignant hyperthermia, susceptibility to, 1

Uncertain:1

Dec 13, 2023

All of Us Research Program, National Institutes of Health

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This missense variant replaces serine with phenylalanine at codon 3448 of the RYR1 protein. Computational prediction suggests that this variant may have deleterious impact on protein structure and function (internally defined REVEL score threshold >= 0.85, PMID: 27666373). To our knowledge, functional studies have not been reported for this variant. This variant has not been reported in individuals affected with autosomal dominant malignant hyperthermia in the literature, although it is associated with other phenotype(s) (ClinVar variation ID: 12991). This variant has not been identified in the general population by the Genome Aggregation Database (gnomAD). Due to insufficient evidence, this variant is classified as a Variant of Uncertain Significance for autosomal dominant malignant hyperthermia.

not provided

Other:1

RYR1 database

Significance:not provided

Review Status:no classification provided

Collection Method:literature only

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

1.0

BayesDel_addAF

Pathogenic

0.52

BayesDel_noAF

Pathogenic

0.51

CADD

Uncertain

(source)

DANN

Benign

0.97

DEOGEN2

Pathogenic

0.86

Eigen

Uncertain

0.67

Eigen_PC

Uncertain

0.54

FATHMM_MKL

Uncertain

0.95

LIST_S2

Pathogenic

1.0

M_CAP

Pathogenic

0.88

MetaRNN

Pathogenic

0.96

MetaSVM

Pathogenic

1.1

MutationAssessor

Uncertain

2.4

PhyloP100

7.8

PrimateAI

Pathogenic

0.80

PROVEAN

Pathogenic

-5.7

REVEL

Pathogenic

0.94

Sift

Pathogenic

0.0

Polyphen

1.0

Vest4

0.85

MutPred

0.79

Loss of disorder (P = 0.0352)

MVP

0.95

MPC

0.41

ClinPred

1.0

GERP RS

2.9

Varity_R

0.79

gMVP

0.84

Mutation Taster

=0/100

disease causing (ClinVar)

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

Splicevardb

2.0

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over