rs111364296

Positions:

Variant summary

Our verdict is Uncertain significance. Variant got 3 ACMG points: 3P and 0B. PM1PP1

This summary comes from the ClinGen Evidence Repository: 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 glutamic acid with lysine at codon 2404 of the RYR1 protein, p.(Glu2404Lys). The maximum allele frequency for this variant among the six major gnomAD populations is AFR: 0.000127, a frequency consistent with pathogenicity for MHS. This variant has been reported in an individual with a personal or family history of an MH episode and a positive in vitro contracture test (IVCT) or caffeine halothane contracture test (CHCT) result (if the proband was unavailable for testing, a positive diagnostic test result in a mutation-positive relative was counted) (PMID:19191329). However, the high MAF in the AFR population in gnomAD precludes the use of PS4. An ex vivo assay in lymphoblasts from multiple related individuals showed an increased sensitivity to RYR1 agonists but this does not meet the criteria for PS3 which requires samples from multiple unrelated individuals to be tested (PMID:19191329). This variant resides in a region of RYR1 considered to be a hotspot for pathogenic variants that contribute to MHS, PM1 (PMID:21118704). This variant segregates with MHS in three individuals, PP1_Supporting (PMID:19191329). A REVEL score of 0.676 supports neither a pathogenic nor a benign status for this variant. This variant has been classified as a Variant of Unknown Significance. Criteria implemented: PM1, PP1_Supporting. LINK:https://erepo.genome.network/evrepo/ui/classification/CA024723/MONDO:0007783/012

Frequency

Genomes: 𝑓 0.000026 ( 0 hom., cov: 32)

Exomes 𝑓: 0.000017 ( 0 hom. )

Consequence

RYR1
NM_000540.3 missense

Scores

Clinical Significance

Uncertain significance reviewed by expert panel P:1U:4

Conservation

PhyloP100: 2.97

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 3 ACMG points.

PM1

For more information check the summary or visit ClinGen Evidence Repository.

PP1

For more information check the summary or visit ClinGen Evidence Repository.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
RYR1	NM_000540.3 linkuse as main transcript	c.7210G>A	p.Glu2404Lys	missense_variant	44/106	ENST00000359596.8	NP_000531.2	P21817-1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	UniProt
RYR1	ENST00000359596.8 linkuse as main transcript	c.7210G>A	p.Glu2404Lys	missense_variant	44/106	5	NM_000540.3	ENSP00000352608.2	P21817-1
RYR1	ENST00000355481.8 linkuse as main transcript	c.7210G>A	p.Glu2404Lys	missense_variant	44/105	1		ENSP00000347667.3	P21817-2
RYR1	ENST00000594335.5 linkuse as main transcript	n.661G>A		non_coding_transcript_exon_variant	5/49	1		ENSP00000470927.2	M0R014
RYR1	ENST00000599547.6 linkuse as main transcript	n.7210G>A		non_coding_transcript_exon_variant	44/80	2		ENSP00000471601.2	M0R127

Frequencies

GnomAD3 genomes

AF:

0.0000263

AC:

AN:

152122

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000483

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.0000654

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:

0.0000295

AC:

AN:

237118

Hom.:

AF XY:

0.0000231

AC XY:

AN XY:

129842

show subpopulations

Gnomad AFR exome

AF:

0.0000669

Gnomad AMR exome

AF:

0.0000294

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.0000556

Gnomad SAS exome

AF:

0.0000331

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000187

Gnomad OTH exome

AF:

0.000171

GnomAD4 exome

AF:

0.0000172

AC:

AN:

1454568

Hom.:

Cov.:

AF XY:

0.0000207

AC XY:

AN XY:

723730

show subpopulations

Gnomad4 AFR exome

AF:

0.0000599

Gnomad4 AMR exome

AF:

0.0000224

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.0000581

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.0000135

Gnomad4 OTH exome

AF:

0.0000333

GnomAD4 genome

AF:

0.0000263

AC:

AN:

152122

Hom.:

Cov.:

AF XY:

0.0000269

AC XY:

AN XY:

74310

show subpopulations

Gnomad4 AFR

AF:

0.0000483

Gnomad4 AMR

AF:

0.0000654

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

Bravo

AF:

0.0000453

ESP6500AA

AF:

0.00

AC:

ESP6500EA

AF:

0.000116

AC:

ExAC

AF:

0.0000248

AC:

ClinVar

Significance: Uncertain significance

Submissions summary: Pathogenic:1Uncertain:4

Revision: reviewed by expert panel

LINK: link

Submissions by phenotype

Malignant hyperthermia, susceptibility to, 1

Uncertain:3

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 glutamic acid with lysine at codon 2404 of the RYR1 protein, p.(Glu2404Lys). The maximum allele frequency for this variant among the six major gnomAD populations is AFR: 0.000127, a frequency consistent with pathogenicity for MHS. This variant has been reported in an individual with a personal or family history of an MH episode and a positive in vitro contracture test (IVCT) or caffeine halothane contracture test (CHCT) result (if the proband was unavailable for testing, a positive diagnostic test result in a mutation-positive relative was counted) (PMID:19191329). However, the high MAF in the AFR population in gnomAD precludes the use of PS4. An ex vivo assay in lymphoblasts from multiple related individuals showed an increased sensitivity to RYR1 agonists but this does not meet the criteria for PS3 which requires samples from multiple unrelated individuals to be tested (PMID:19191329). This variant resides in a region of RYR1 considered to be a hotspot for pathogenic variants that contribute to MHS, PM1 (PMID: 21118704). This variant segregates with MHS in three individuals, PP1_Supporting (PMID:19191329). A REVEL score of 0.676 supports neither a pathogenic nor a benign status for this variant. This variant has been classified as a Variant of Unknown Significance. Criteria implemented: PM1, PP1_Supporting. -
Uncertain significance, criteria provided, single submitter	clinical testing	All of Us Research Program, National Institutes of Health	Sep 23, 2024	This missense variant replaces glutamic acid with lysine at codon 2404 of the RYR1 protein. Computational prediction is inconclusive regarding the impact of this variant on protein structure and function (internally defined REVEL score threshold 0.5 < inconclusive < 0.7, PMID: 27666373). A functional study on patient-derived lymphoblastoid cells showed this variant increases sensitivity to caffeine but not 4-CmC compared to cells carrying wild-type RYR1 (PMID: 19191329). This variant has been reported in a family affected with malignant hyperthermia susceptibility (PMID: 19191329). This variant has been identified in 9/268418 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. -

RYR1-related disorder

Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Jul 31, 2023

For these reasons, this variant has been classified as Pathogenic. 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. ClinVar contains an entry for this variant (Variation ID: 161379). This missense change has been observed in individual(s) with autosomal dominant malignant hyperthermia and/or statin-associated muscle symptoms (PMID: 19191329, 30325262). It has also been observed to segregate with disease in related individuals. This variant is present in population databases (rs111364296, gnomAD 0.01%). This sequence change replaces glutamic acid, which is acidic and polar, with lysine, which is basic and polar, at codon 2404 of the RYR1 protein (p.Glu2404Lys). -

not specified

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Jul 30, 2024

Variant summary: RYR1 c.7210G>A (p.Glu2404Lys) results in a conservative amino acid change in the encoded protein sequence. Three of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 3e-05 in 237118 control chromosomes. c.7210G>A has been reported in the literature in individuals affected with Malignant Hyperthermia Susceptibility (Levano_2009). These data indicate that the variant may be associated with disease. It has also been observed in individuals with statin-associated muscle spasms (Isackson_2018) and facioscapulohumeral muscular dystrophy (Erdmann_2023). To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. The following publications have been ascertained in the context of this evaluation (PMID: 36100962, 30325262, 19191329). ClinVar contains an entry for this variant (Variation ID: 161379). Based on the evidence outlined above, the variant was classified as VUS-possibly pathogenic. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.19

BayesDel_addAF

Pathogenic

0.26

BayesDel_noAF

Pathogenic

0.32

CADD

Benign

DANN

Uncertain

1.0

DEOGEN2

Uncertain

0.43

.;T

Eigen

Benign

-0.027

Eigen_PC

Benign

-0.012

FATHMM_MKL

Uncertain

0.93

LIST_S2

Uncertain

0.88

D;D

M_CAP

Uncertain

0.25

MetaRNN

Uncertain

0.72

D;D

MetaSVM

Pathogenic

0.85

MutationAssessor

Benign

1.4

L;L

PrimateAI

Uncertain

0.71

PROVEAN

Benign

-1.4

N;N

REVEL

Pathogenic

0.68

Sift

Benign

0.76

T;T

Polyphen

0.79

P;D

Vest4

0.69

MVP

0.97

MPC

0.36

ClinPred

0.053

GERP RS

3.7

Varity_R

0.18

gMVP

0.66

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