rs144685735

Variant summary

Our verdict is Uncertain significance. Variant got 5 ACMG points: 5P and 0B. PM1PP2PP3_Moderate

The NM_000540.3(RYR1):c.12121C>T(p.Arg4041Trp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000149 in 1,614,046 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. R4041Q) has been classified as Uncertain significance.

Frequency

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

Exomes 𝑓: 0.000016 ( 0 hom. )

Consequence

RYR1
NM_000540.3 missense

Scores

Clinical Significance

Uncertain significance reviewed by expert panel U:8O:1

Conservation

PhyloP100: 1.19

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 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 5 ACMG points.

PM1

In a hotspot region, there are 2 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 1 benign, 6 uncertain in NM_000540.3

PP2

Missense variant where missense usually causes diseases, RYR1

PP3

MetaRNN computational evidence supports a deleterious effect, 0.85

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
RYR1	NM_000540.3 linkuse as main transcript	c.12121C>T	p.Arg4041Trp	missense_variant	89/106	ENST00000359596.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
RYR1	ENST00000359596.8 linkuse as main transcript	c.12121C>T	p.Arg4041Trp	missense_variant	89/106	5	NM_000540.3	A2	P21817-1

Frequencies

GnomAD3 genomes

AF:

0.00000657

AC:

AN:

152164

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

GnomAD3 exomes

AF:

0.0000119

AC:

AN:

251464

Hom.:

AF XY:

0.00000736

AC XY:

AN XY:

135912

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 SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000264

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000157

AC:

AN:

1461882

Hom.:

Cov.:

AF XY:

0.0000151

AC XY:

AN XY:

727240

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.0000504

Gnomad4 SAS exome

AF:

0.0000116

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.0000180

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

AF:

0.00000657

AC:

AN:

152164

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

74346

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000147

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.0000236

Hom.:

Bravo

AF:

0.0000189

ESP6500AA

AF:

0.00

AC:

ESP6500EA

AF:

0.000233

AC:

ExAC

AF:

0.0000247

AC:

EpiCase

AF:

0.0000545

EpiControl

AF:

0.0000593

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:8Other:1

Revision: reviewed by expert panel

LINK: link

Submissions by phenotype

Malignant hyperthermia, susceptibility to, 1

Uncertain:4

Uncertain significance, criteria provided, single submitter	clinical testing	Molecular Genetics, Royal Melbourne Hospital	Apr 11, 2024	This sequence change in RYR1 is predicted to replace arginine with tryptophan at codon 4041, p.(Arg4041Trp). The arginine residue is highly conserved (100 vertebrates, UCSC), and is located in exon 89 upstream of the C-terminal region hotspot. There is a large physicochemical difference between arginine and tryptophan. The highest population minor allele frequency in the population database gnomAD v2.1 is 0.003% (3/113,746 alleles) in the European (non-Finnish) population, which is consistent with malignant hyperthermia. This variant has been identified in at least two probands with positive in vitro contracture test (IVCT) results, although a malignant hyperthermia (MH) event has only been confirmed in one of the individuals (PMID: 16835904; Royal Melbourne Hospital). The variant has been reported to segregate with RYR1-related disease in two families (PMID: 16835904; Invitae - ClinVar: SCV001389012.3). Multiple lines of computational evidence have conflicting predictions for the missense substitution (3/5 algorithms predict deleterious). Based on the classification scheme RMH Modified ACMG Guidelines v1.5.1, this variant is classified as a VARIANT OF UNCERTAIN SIGNIFICANCE. Following criteria are met: PP1_Moderate, PS4_Supporting. -
Uncertain significance, no assertion criteria provided	research	CSER _CC_NCGL, University of Washington	Jun 01, 2014	- -
Uncertain significance, reviewed by expert panel	curation	ClinGen Malignant Hyperthermia Susceptibility Variant Curation Expert Panel, ClinGen	Apr 06, 2023	This pathogenicity assessment is relevant only for malignant hyperthermia susceptibility (MHS) inherited in an autosomal dominant pattern. Variants in RYR1 can also cause other myopathies inherited in an autosomal dominant pattern or in an autosomal recessive pattern. Some of these disorders may predispose individuals to malignant hyperthermia. RYR1 variants may also contribute to a malignant hyperthermia reaction in combination with other genetic and non-genetic factors and the clinician needs to consider such factors in making management decisions. This sequence variant predicts a substitution of arginine with tryptophan at codon 4041 of the RYR1 protein, p.(Arg4041Trp). The maximum allele frequency for this variant among the six major gnomAD populations is NFE: 0.000026, a frequency consistent with pathogenicity for MHS. This variant has been reported in an individual without a clear personal or family history of an MH episode, the individual had a positive in vitro contracture test (IVCT) result, this does not meet PS4 (PMID:16835904). No functional studies were identified for this variant. This variant does not reside in a hotspot for pathogenic variants that contribute to MHS. A REVEL score <0.5 (0.435) supports a benign status for this variant, BP4. This variant has been classified as a Variant of Unknown Significance. Criteria implemented: BP4. -
Uncertain significance, criteria provided, single submitter	clinical testing	All of Us Research Program, National Institutes of Health	Dec 01, 2023	This missense variant replaces arginine with tryptophan at codon 4041 of the RYR1 protein. Computational prediction suggests that this variant may not impact protein structure and function (internally defined REVEL score threshold <= 0.5, PMID: 27666373). To our knowledge, functional studies have not been reported for this variant. This variant has been reported in an individual affected with malignant hyperthermia susceptibility (PMID: 16835904). This variant has been identified in 3/251464 chromosomes in the general population by the Genome Aggregation Database (gnomAD). The available evidence is insufficient to determine the role of this variant in disease conclusively. Therefore, this variant is classified as a Variant of Uncertain Significance. -

not provided

Uncertain:3Other:1

Uncertain significance, criteria provided, single submitter	clinical testing	GeneDx	Oct 07, 2022	Not observed at a significant frequency in large population cohorts (gnomAD); In silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect; This variant is associated with the following publications: (PMID: 25637381, 24055113, 16835904) -
Uncertain significance, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Apr 15, 2015	- -
not provided, no classification provided	literature only	Leiden Muscular Dystrophy (RYR1)	-	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Revvity Omics, Revvity	Jul 18, 2019	- -

RYR1-related disorder

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Invitae

Oct 25, 2022

This sequence change replaces arginine, which is basic and polar, with tryptophan, which is neutral and slightly polar, at codon 4041 of the RYR1 protein (p.Arg4041Trp). This variant is present in population databases (rs144685735, gnomAD 0.002%). This missense change has been observed in individual(s) with malignant hyperthermia (PMID: 16835904). ClinVar contains an entry for this variant (Variation ID: 133032). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) has been performed at Invitae for this missense variant, however the output from this modeling did not meet the statistical confidence thresholds required to predict the impact of this variant on RYR1 protein function. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.66

BayesDel_addAF

Pathogenic

0.25

BayesDel_noAF

Pathogenic

0.14

Cadd

Uncertain

Dann

Uncertain

0.98

Eigen

Uncertain

0.36

Eigen_PC

Uncertain

0.31

FATHMM_MKL

Benign

0.75

LIST_S2

Pathogenic

0.99

D;D

M_CAP

Uncertain

0.18

MetaRNN

Pathogenic

0.85

D;D

MetaSVM

Uncertain

-0.20

MutationTaster

Benign

0.94

D;D;D

PrimateAI

Uncertain

0.74

PROVEAN

Pathogenic

-5.5

D;D

REVEL

Uncertain

0.43

Sift

Pathogenic

0.0

D;D

Polyphen

1.0

D;D

Vest4

0.84

MVP

0.96

MPC

0.60

ClinPred

0.99

GERP RS

3.1

Varity_R

0.54

gMVP

0.81

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

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over