rs766407858

Variant names:

Variant summary

Our verdict is Likely pathogenic. The variant received 7 ACMG points: 7P and 0B. PM1PP3_StrongPP5

The NM_000540.3(RYR1):c.122T>C(p.Phe41Ser) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000048 in 1,457,826 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 Conflicting classifications of pathogenicity (no stars). Synonymous variant affecting the same amino acid position (i.e. F41F) has been classified as Likely benign.

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 0.0000048 ( 0 hom. )

Consequence

RYR1
NM_000540.3 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:2U:2

Conservation

PhyloP100: 7.87

Publications

5 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: Likely_pathogenic. The variant received 7 ACMG points.

PM1

In a hotspot region, there are 6 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 15 uncertain in NM_000540.3

PP3

MetaRNN computational evidence supports a deleterious effect, 0.94

PP5

Variant 19-38440821-T-C is Pathogenic according to our data. Variant chr19-38440821-T-C is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 478170.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
RYR1	NM_000540.3 link	c.122T>C	p.Phe41Ser	missense_variant	Exon 2 of 106	ENST00000359596.8	NP_000531.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
RYR1	ENST00000359596.8 link	c.122T>C	p.Phe41Ser	missense_variant	Exon 2 of 106	5	NM_000540.3	ENSP00000352608.2

Frequencies

GnomAD3 genomes

Cov.:

GnomAD2 exomes

AF:

0.0000210

AC:

AN:

238280

AF XY:

0.0000153

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.000148

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:

0.00000480

AC:

AN:

1457826

Hom.:

Cov.:

AF XY:

0.00000552

AC XY:

AN XY:

725066

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

33460

American (AMR)

AF:

0.000113

AC:

AN:

44280

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

25912

East Asian (EAS)

AF:

0.00

AC:

AN:

39654

South Asian (SAS)

AF:

0.00

AC:

AN:

85682

European-Finnish (FIN)

AF:

0.00

AC:

AN:

52034

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5628

European-Non Finnish (NFE)

AF:

0.00000180

AC:

AN:

1110990

Other (OTH)

AF:

0.00

AC:

AN:

60186

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.446

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

Cov.:

Alfa

AF:

0.0000359

Hom.:

Bravo

AF:

0.0000113

ExAC

AF:

0.0000414

AC:

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:2Uncertain:2

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

not provided

Pathogenic:1Uncertain:1

Nov 21, 2016

PreventionGenetics, part of Exact Sciences

Significance:Likely pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Jul 21, 2020

Revvity Omics, Revvity

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

RYR1-related disorder

Pathogenic:1

Jan 27, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This sequence change replaces phenylalanine, which is neutral and non-polar, with serine, which is neutral and polar, at codon 41 of the RYR1 protein (p.Phe41Ser). This variant is present in population databases (rs766407858, gnomAD 0.02%). This missense change has been observed in individuals with autosomal recessive congenital myopathy (PMID: 21911697, 23553484; internal data). ClinVar contains an entry for this variant (Variation ID: 478170). Invitae Evidence Modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) indicates that this missense variant is expected to disrupt RYR1 protein function with a positive predictive value of 95%. For these reasons, this variant has been classified as Pathogenic. -

Malignant hyperthermia, susceptibility to, 1

Uncertain:1

Jun 09, 2024

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 phenylalanine with serine at codon 41 of the RYR1 protein. Computational prediction suggests that this variant may have deleterious impact on protein structure and function. 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: 478170; PMID: 21911697, 23553484, 33458582, 33333461). This variant has been identified in 5/238280 chromosomes 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. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.95

BayesDel_addAF

Pathogenic

0.37

BayesDel_noAF

Pathogenic

0.55

CADD

Uncertain

(source)

DANN

Benign

0.95

DEOGEN2

Pathogenic

0.90

.;D

Eigen

Uncertain

0.60

Eigen_PC

Uncertain

0.50

FATHMM_MKL

Pathogenic

0.98

LIST_S2

Uncertain

0.94

D;D

M_CAP

Pathogenic

0.99

MetaRNN

Pathogenic

0.94

D;D

MetaSVM

Pathogenic

1.1

MutationAssessor

Uncertain

2.5

M;M

PhyloP100

7.9

PrimateAI

Uncertain

0.78

PROVEAN

Pathogenic

-5.2

D;D

REVEL

Pathogenic

0.93

Sift

Pathogenic

0.0

D;D

Polyphen

1.0

D;D

Vest4

0.83

MVP

0.96

MPC

1.4

ClinPred

0.94

GERP RS

4.9

Varity_R

0.88

gMVP

0.86

Mutation Taster

=0/100

disease causing (ClinVar)

(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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over