rs193922879

Variant summary

Our verdict is Likely pathogenic. Variant got 9 ACMG points: 9P and 0B. PM1PP2PP3_ModeratePP5_Strong

The NM_000540.3(RYR1):c.14524G>A(p.Val4842Met) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000967 in 1,613,970 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. V4842A) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.00011 ( 0 hom., cov: 31)

Exomes 𝑓: 0.000096 ( 0 hom. )

Consequence

RYR1
NM_000540.3 missense

Scores

Clinical Significance

Uncertain significance reviewed by expert panel P:2U:13O:1

Conservation

PhyloP100: 9.95

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 Likely_pathogenic. Variant got 9 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, 6 uncertain in NM_000540.3

PP2

Missense variant where missense usually causes diseases, RYR1

PP3

MetaRNN computational evidence supports a deleterious effect, 0.86

PP5

Variant 19-38580382-G-A is Pathogenic according to our data. Variant chr19-38580382-G-A is described in ClinVar as [Uncertain_significance]. Clinvar id is 133075.Status of the report is reviewed_by_expert_panel, 3 stars. We mark this variant Likely_pathogenic, oryginal submissions are: {Uncertain_significance=12, not_provided=1, Likely_pathogenic=2}. Variant chr19-38580382-G-A is described in Lovd as [Pathogenic]. Variant chr19-38580382-G-A is described in Lovd as [Likely_pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
RYR1	NM_000540.3 linkuse as main transcript	c.14524G>A	p.Val4842Met	missense_variant	101/106	ENST00000359596.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
RYR1	ENST00000359596.8 linkuse as main transcript	c.14524G>A	p.Val4842Met	missense_variant	101/106	5	NM_000540.3	A2	P21817-1

Frequencies

GnomAD3 genomes

AF:

0.000105

AC:

AN:

152158

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000266

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.000864

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.000207

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000147

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000756

AC:

AN:

251266

Hom.:

AF XY:

0.0000515

AC XY:

AN XY:

135818

show subpopulations

Gnomad AFR exome

AF:

0.000185

Gnomad AMR exome

AF:

0.0000289

Gnomad ASJ exome

AF:

0.000794

Gnomad EAS exome

AF:

0.0000544

Gnomad SAS exome

AF:

0.0000980

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000264

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000958

AC:

140

AN:

1461812

Hom.:

Cov.:

AF XY:

0.0000880

AC XY:

AN XY:

727204

show subpopulations

Gnomad4 AFR exome

AF:

0.000418

Gnomad4 AMR exome

AF:

0.0000224

Gnomad4 ASJ exome

AF:

0.000803

Gnomad4 EAS exome

AF:

0.0000756

Gnomad4 SAS exome

AF:

0.000104

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.0000603

Gnomad4 OTH exome

AF:

0.000364

GnomAD4 genome

AF:

0.000105

AC:

AN:

152158

Hom.:

Cov.:

AF XY:

0.000108

AC XY:

AN XY:

74328

show subpopulations

Gnomad4 AFR

AF:

0.000266

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.000864

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.000207

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000147

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.000117

Hom.:

Bravo

AF:

0.000125

ESP6500AA

AF:

0.000227

AC:

ESP6500EA

AF:

0.00

AC:

ExAC

AF:

0.0000576

AC:

EpiCase

AF:

0.0000545

EpiControl

AF:

0.0000593

ClinVar

Significance: Uncertain significance

Submissions summary: Pathogenic:2Uncertain:13Other:1

Revision: reviewed by expert panel

LINK: link

Submissions by phenotype

not provided

Pathogenic:1Uncertain:3Other:1

not provided, no classification provided	literature only	Leiden Muscular Dystrophy (RYR1)	-	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Athena Diagnostics	Feb 21, 2023	Available data are insufficient to determine the clinical significance of the variant at this time. The frequency of this variant in the general population is uninformative in assessment of its pathogenicity (http://gnomad.broadinstitute.org). Computational tools predict that this variant is damaging. -
Uncertain significance, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Aug 15, 2017	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Revvity Omics, Revvity	Mar 15, 2022	- -
Likely pathogenic, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Jul 01, 2019	- -

Malignant hyperthermia, susceptibility to, 1

Uncertain:3

Uncertain significance, criteria provided, single submitter	clinical testing	All of Us Research Program, National Institutes of Health	Dec 13, 2023	This missense variant replaces valine with methionine at codon 4842 of the RYR1 protein. Computational prediction suggests that this variant may have deleterious impact on protein structure and function (internally defined REVEL score threshold >= 0.7, PMID: 27666373). To our knowledge, functional studies have not been reported for this variant. This variant has been reported in one individual affected with autosomal dominant malignant hyperthermia (PMID: 21455645). This variant has been associated with other phenotype(s) (ClinVar Variation ID: 133075). This variant has been identified in 21/282634 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. -
Uncertain significance, criteria provided, single submitter	clinical testing	Color Diagnostics, LLC DBA Color Health	May 08, 2023	This missense variant replaces valine with methionine at codon 4842 of the RYR1 protein. Computational prediction suggests that this variant may have deleterious impact on protein structure and function (internally defined REVEL score threshold >= 0.7, PMID: 27666373). To our knowledge, functional studies have not been reported for this variant. This variant has been reported in one individual affected with autosomal dominant malignant hyperthermia (PMID: 21455645). This variant has been associated with other phenotype(s) (ClinVar Variation ID: 133075). This variant has been identified in 21/282634 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. -
Uncertain significance, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Apr 27, 2017	This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). No publications were found based on this search. Allele frequency data from public databases did not allow this variant to be ruled in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance. -

RYR1-related disorder

Uncertain:3

Uncertain significance, criteria provided, single submitter	clinical testing	Invitae	Oct 25, 2022	This sequence change replaces valine, which is neutral and non-polar, with methionine, which is neutral and non-polar, at codon 4842 of the RYR1 protein (p.Val4842Met). This variant is present in population databases (rs193922879, gnomAD 0.07%). This missense change has been observed in individual(s) with with autosomal recessive congenital myopathy and an individual affected with malignant hyperthermia susceptibility. In some cases, this variant occurred on the same chromosome as the c.10348‚Äì6C>G variant (PMID: 18253926, 20839240, 21062345, 21455645, 23394784, 23553484, 23553787, 26019235, 27854218, 28818389). ClinVar contains an entry for this variant (Variation ID: 133075). 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) performed at Invitae indicates that this missense variant is expected to disrupt 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. -
Uncertain significance, criteria provided, single submitter	research	Division of Human Genetics, National Health Laboratory Service/University of the Witwatersrand	Jul 01, 2023	- -
Uncertain significance, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	Feb 02, 2024	The RYR1 c.14524G>A variant is predicted to result in the amino acid substitution p.Val4842Met. This variant, along with the c.10348-6C>G variant on the same allele, has been documented in at least three unrelated families with autosomal recessive RYR1-related congenital myopathy (Monnier et al. 2008. PubMed ID: 18253926; Wilmshurst et al. 2010. PubMed ID: 20839240; Bevilacqua et al. 2011. PubMed ID: 21062345). The c.10348-6C>G variant is predicted to weaken the canonical acceptor splice site at the junction of intron 68 and exon 69 based on available splicing prediction programs (Alamut Visual v2.11). The c.14524G>A (p.Val4842Met) has been classified as a variant of uncertain clinical significance by the ClinGen Malignant Hyperthermia Susceptibility Variant Curation Expert Panel (https://www.ncbi.nlm.nih.gov/clinvar/variation/133075/). This variant is reported in 0.077% of alleles in individuals of Ashkenazi Jewish descent in gnomAD. While the clinical significance of the c.14524G>A variant by itself is uncertain, we classify this combined haplotype (c.10348-6G>C and c.14524G>A (p.Val4842Met)) as pathogenic. -

Neuromuscular disease

Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Nov 03, 2022

The p.Val4842Met variant in RYR1 has been reported in compound heterozygosity in 13 individuals with centronuclear myopathy (Monneri 2008 PMID: 18253926, Wilmshurst 2010 PMID: 20839240, Bevilacqua 2011 PMID: 21062345). This variant segregated with disease in 3 affected relatives with centronuclear myopathy in 2 families. In the 13 individuals with centronuclear myopathy, the p.Val4842Met variant always occurred in conjunction with the c.10348-6C>G variant on the same copy of the gene (in cis). The p.Val4842Met variant has also been identified in 2/10334 of African chromosomes by the Exome Aggregation Consortium (ExAC, http://exac.broadinstitute.org; dbSNP rs193922879). Computational prediction tools and conservation analysis suggest that the p.Val4842Met variant may impact the protein, though this information is not predictive enough to determine pathogenicity. In summary, although additional studies are required to fully establish its clinical significance, the p.Val4842Met variant is likely pathogenic for centronuclear myopathy in an autosomal recessive manner. ACMG/AMP criteria applied: PM3_Strong, PP1, PP3. -

not specified

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Mendelics

May 04, 2022

- -

Congenital myopathy with cores

Uncertain:1

Uncertain significance, no assertion criteria provided

research

CSER _CC_NCGL, University of Washington

Jun 01, 2014

- -

Malignant hyperthermia of anesthesia

Uncertain:1

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 valine with methionine at codon 4842 of the RYR1 protein, p.(Val4842Met). The maximum allele frequency for this variant among the six major gnomAD populations is AFR: 0.0002, 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:21455645). However, the high MAF in the AFR population in gnomAD precludes the use of PS4. No functional studies were identified for this variant. This variant resides in a region of RYR1 considered to be a hotspot for pathogenic variants that contribute to MHS, PM1_Supporting (PMID: 21118704). A REVEL score >0.85 (0.933) supports a pathogenic status for this variant, PP3_Moderate. This variant has been classified as a Variant of Unknown Significance. Criteria implemented: PM1_Supporting, PP3_Moderate. -

Congenital myopathy with fiber type disproportion;C0751951:Central core myopathy;C1840365:King Denborough syndrome;C1850674:Congenital multicore myopathy with external ophthalmoplegia;C2930980:Malignant hyperthermia, susceptibility to, 1

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Fulgent Genetics, Fulgent Genetics

Sep 27, 2021

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.68

BayesDel_addAF

Pathogenic

0.31

BayesDel_noAF

Pathogenic

0.49

Cadd

Pathogenic

Dann

Benign

0.93

Eigen

Pathogenic

0.84

Eigen_PC

Pathogenic

0.79

FATHMM_MKL

Pathogenic

1.0

LIST_S2

Pathogenic

0.99

D;D

M_CAP

Pathogenic

0.86

MetaRNN

Pathogenic

0.86

D;D

MetaSVM

Pathogenic

1.1

MutationTaster

Benign

1.0

D;D;D

PrimateAI

Pathogenic

0.81

PROVEAN

Uncertain

-2.6

D;D

REVEL

Pathogenic

0.93

Sift

Uncertain

0.0010

D;D

Polyphen

1.0

D;D

Vest4

0.74

MVP

0.98

MPC

1.0

ClinPred

0.69

GERP RS

4.6

Varity_R

0.59

gMVP

0.93

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