rs193922781

Positions:

chr19-38485838-C-T

Variant summary

Our verdict is Likely pathogenic. Variant got 7 ACMG points: 8P and 1B. BP4PS4PP1_Strong

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 Serine with Phenylalanine at codon 1728 of the RYR1 protein, p.(Ser1728Phe). The maximum allele frequency for this variant among the six major gnomAD populations is AMR: MAF 0.000029, a frequency consistent with pathogenicity for MHS. This variant has been reported in nine unrelated individuals who have a personal or family history of a malignant hyperthermia reaction, nine of these individuals had 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), PS4 (PMID:30236257; PMID:15731587). This variant segregates with MHS in five families, PP1_Strong (PMID:30236257). 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 supports a benign status for this variant, BP4. Based on using Bayes to combine criteria this variant is assessed as Likely Pathogenic, (PMID:29300386). Criteria implemented: PS4, PP1_Strong, BP4. LINK:https://erepo.genome.network/evrepo/ui/classification/CV133144/MONDO:0007783/012

Frequency

Genomes: 𝑓 0.000013 ( 0 hom., cov: 32)

Exomes 𝑓: 0.000038 ( 0 hom. )

Consequence

RYR1
NM_000540.3 missense

Scores

Clinical Significance

Likely pathogenic reviewed by expert panel P:13O:1

Conservation

PhyloP100: 1.26

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 7 ACMG points.

PS4

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

PP1

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

BP4

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.5183C>T	p.Ser1728Phe	missense_variant	34/106	ENST00000359596.8	NP_000531.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
RYR1	ENST00000359596.8 linkuse as main transcript	c.5183C>T	p.Ser1728Phe	missense_variant	34/106	5	NM_000540.3	ENSP00000352608	A2	P21817-1
RYR1	ENST00000355481.8 linkuse as main transcript	c.5183C>T	p.Ser1728Phe	missense_variant	34/105	1		ENSP00000347667	P4	P21817-2
RYR1	ENST00000599547.6 linkuse as main transcript	c.5183C>T	p.Ser1728Phe	missense_variant, NMD_transcript_variant	34/80	2		ENSP00000471601

Frequencies

GnomAD3 genomes

AF:

0.0000131

AC:

AN:

152206

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:

0.0000294

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.00000406

AC:

AN:

246040

Hom.:

AF XY:

0.00000750

AC XY:

AN XY:

133290

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.0000290

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:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000383

AC:

AN:

1461502

Hom.:

Cov.:

AF XY:

0.0000303

AC XY:

AN XY:

727058

show subpopulations

Gnomad4 AFR exome

AF:

0.0000299

Gnomad4 AMR exome

AF:

0.0000224

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.0000486

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

AF:

0.0000131

AC:

AN:

152206

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

74358

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:

0.0000294

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.0000489

Hom.:

Bravo

AF:

0.0000189

ESP6500AA

AF:

0.00

AC:

ESP6500EA

AF:

0.000116

AC:

EpiCase

AF:

0.0000545

EpiControl

AF:

0.00

ClinVar

Significance: Likely pathogenic

Submissions summary: Pathogenic:13Other:1

Revision: reviewed by expert panel

LINK: link

Submissions by phenotype

Malignant hyperthermia, susceptibility to, 1

Pathogenic:6

Likely pathogenic, criteria provided, single submitter	research	HudsonAlpha Institute for Biotechnology, HudsonAlpha Institute for Biotechnology	Sep 03, 2020	ACMG codes:PS4, PM2, PP3, PP5 -
Likely pathogenic, reviewed by expert panel	curation	ClinGen Malignant Hyperthermia Susceptibility Variant Curation Expert Panel, ClinGen	May 20, 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 Serine with Phenylalanine at codon 1728 of the RYR1 protein, p.(Ser1728Phe). The maximum allele frequency for this variant among the six major gnomAD populations is AMR: MAF 0.000029, a frequency consistent with pathogenicity for MHS. This variant has been reported in nine unrelated individuals who have a personal or family history of a malignant hyperthermia reaction, nine of these individuals had 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), PS4 (PMID:30236257; PMID:15731587). This variant segregates with MHS in five families, PP1_Strong (PMID:30236257). 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 supports a benign status for this variant, BP4. Based on using Bayes to combine criteria this variant is assessed as Likely Pathogenic, (PMID: 29300386). Criteria implemented: PS4, PP1_Strong, BP4. -
Pathogenic, no assertion criteria provided	research	CSER _CC_NCGL, University of Washington	Jun 01, 2014	- -
Pathogenic, criteria provided, single submitter	clinical testing	National Institute of Allergy and Infectious Diseases - Centralized Sequencing Program, National Institutes of Health	Aug 06, 2021	- -
Pathogenic, criteria provided, single submitter	research	Biesecker Lab/Clinical Genomics Section, National Institutes of Health	Jul 01, 2013	- -
Likely pathogenic, criteria provided, single submitter	clinical testing	Rady Children's Institute for Genomic Medicine, Rady Children's Hospital San Diego	-	This variant has been previously reported as a heterozygous change in patients with malignant hyperthermia (MH) susceptibility (PMID: 19648156, 30236257). In vitro contracture tests have shown this variant may be associated with a weaker MH phenotype (PMID: 19648156). The c.5183C>T (p.Ser1728Phe) variant is present in the heterozygous state in the gnomAD population database at a frequency of 0.0004% (1/246040) and is absent in the homozygous state, thus is presumed to be rare. The c.5183C>T (p.Ser1728Phe) variant affects a moderately conserved amino acid; however, in silico tools used to predict the effect of this variant on protein function yield discordant results. Based on the available evidence, the c.5183C>T (p.Ser1728Phe) variant is classified as Likely Pathogenic. -

not provided

Pathogenic:2Other:1

not provided, no classification provided	literature only	Leiden Muscular Dystrophy (RYR1)	-	- -
Likely pathogenic, criteria provided, single submitter	clinical testing	Revvity Omics, Revvity	Sep 22, 2023	- -
Likely pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Sep 20, 2024	Observed in multiple unrelated patients from different ethnic backgrounds with malignant hyperthermia (MH) in published literature (PMID: 16917943, 30236257, 19648156); Reported in multiple affected individuals from two families with MH; the S1728F variant was associated with a weaker IVCT phenotype compared to other known pathogenic variants in RYR1, suggesting a lesser effect on channel function (PMID: 19648156); Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis indicates that this missense variant does not alter protein structure/function; This variant is associated with the following publications: (PMID: 25637381, 15731587, 24195946, 20566647, 16917943, 30236257, 31559918, 30916033, 34930662, 37787745, 19648156, 38295319, 38542460) -

RYR1-related disorder

Pathogenic:2

Likely pathogenic, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Dec 13, 2023	This sequence change replaces serine, which is neutral and polar, with phenylalanine, which is neutral and non-polar, at codon 1728 of the RYR1 protein (p.Ser1728Phe). This variant is present in population databases (rs193922781, gnomAD 0.003%). This missense change has been observed in individuals with malignant hyperthermia susceptibility (PMID: 16917943, 19648156, 30236257, 31559918). ClinVar contains an entry for this variant (Variation ID: 133144). 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 not expected to disrupt RYR1 protein function with a negative predictive value of 95%. This variant disrupts the p.Ser1728 amino acid residue in RYR1. Other variant(s) that disrupt this residue have been observed in individuals with RYR1-related conditions (PMID: 15731587), which suggests that this may be a clinically significant amino acid residue. In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic. -
Likely pathogenic, no assertion criteria provided	clinical testing	PreventionGenetics, part of Exact Sciences	Sep 03, 2024	The RYR1 c.5183C>T variant is predicted to result in the amino acid substitution p.Ser1728Phe. This variant has been reported to be causative for malignant hyperthermia (MH) in several patients (Robinson et al. 2006. PubMed ID: 16917943; Carpenter et al. 2009. PubMed ID: 19648156). We have also observed this variant in two additional patients at PreventionGenetics (internal data). This variant has been interpreted as likely pathogenic by the the ClinGen Malignant Hyperthermia Susceptibility Variant Curation Expert Panel (https://www.ncbi.nlm.nih.gov/clinvar/variation/133144/). A different substitution at the same amino acid (p.Ser1728Pro) has also been reported to be causative for RYR1-related disorders (Sambuughin et al. 2005. PubMed ID: 15731587). In summary, the c.5183C>T (p.Ser1728Phe) variant is categorized as likely pathogenic. -

Inborn genetic diseases

Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

Ambry Genetics

Aug 04, 2016

- -

Malignant hyperthermia of anesthesia

Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Feb 11, 2020

The p.Ser1728Phe variant in RYR1 has been reported in at least 8 individuals with malignant hyperthermia susceptibility (MH) and segregated with disease in 6 affected family members (Robinson 2006 PMID:16917943, Dalton 2007 (thesis), Carpenter 2009 PMID 19648156, Miller 2018 PMID 30236257). In one family, it was reported not to segregate clearly with disease (with phenotyping based on in vitro contracture tests; IVCT) but no specific details were provided (Miller 2018 PMID 30236257). In addition, it has been reported at least 1 individual with no personal or family history of MH (Gonsalves 2013 PMID 24195946), was identified in 1/34500 Latino chromosomes by gnomAD (http://gnomad.broadinstitute.org/) and has also been reported in ClinVar (Variation ID 133144). Notably, IVCT performed on muscle tissue from individuals carrying this variant suggest that the p.Ser1728Phe variant may be associated with weaker MH phenotypes (Carpenter 2009 PMID 19648156). Computational prediction tools and conservation analysis suggest that the variant may not impact the protein. In summary, although additional studies are required to fully establish its clinical significance, this variant meets criteria to be classified as likely pathogenic for autosomal dominant MH with a less severe phenotype than other disease causing RYR1 variants. ACMG/AMP Criteria applied: PM2, PS4_Moderate, PP1_Moderate, PS3_Moderate, BP4. -

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

Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

Fulgent Genetics, Fulgent Genetics

Oct 22, 2021

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Uncertain

0.49

BayesDel_addAF

Uncertain

0.071

BayesDel_noAF

Uncertain

-0.050

CADD

Uncertain

DANN

Uncertain

1.0

DEOGEN2

Uncertain

0.44

.;T

Eigen

Uncertain

0.28

Eigen_PC

Uncertain

0.26

FATHMM_MKL

Benign

0.34

LIST_S2

Benign

0.84

T;T

M_CAP

Uncertain

0.091

MetaRNN

Uncertain

0.71

D;D

MetaSVM

Benign

-0.67

MutationAssessor

Benign

1.4

L;L

MutationTaster

Benign

0.83

N;N;N

PrimateAI

Uncertain

0.57

PROVEAN

Benign

-1.5

N;N

REVEL

Uncertain

0.48

Sift

Benign

0.40

T;T

Polyphen

0.99

D;D

Vest4

0.56

MVP

0.84

MPC

0.82

ClinPred

0.62

GERP RS

3.8

Varity_R

0.12

gMVP

0.65

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