NM_000540.3:c.5183C>T

Variant names:

• chr19-38485838-C-T
• rs193922781
• NM_000540.3:c.5183C>T

Variant summary

Our verdict is Likely pathogenic. Variant got 7 ACMG points: 8P and 1B. BP4 PS4 PP1_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
• Clinical Significance: Likely pathogenic reviewed by expert panel P:14 O:1
• Conservation: PhyloP100: 1.26

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]

ACMG classification

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 rank	MANE	Protein	UniProt
RYR1	NM_000540.3	c.5183C>T	p.Ser1728Phe	missense_variant	Exon 34 of 106	ENST00000359596.8	NP_000531.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
RYR1	ENST00000359596.8	c.5183C>T	p.Ser1728Phe	missense_variant	Exon 34 of 106	5	NM_000540.3	ENSP00000352608.2
RYR1	ENST00000355481.8	c.5183C>T	p.Ser1728Phe	missense_variant	Exon 34 of 105	1		ENSP00000347667.3
RYR1	ENST00000599547.6	n.5183C>T		non_coding_transcript_exon_variant	Exon 34 of 80	2		ENSP00000471601.2

Frequencies

GnomAD3 genomes AF: 0.0000131 AC: 2 AN: 152206 Hom.: 0 Cov.: 32

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: 1 AN: 246040 Hom.: 0 AF XY: 0.00000750 AC XY: 1 AN XY: 133290

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: 56 AN: 1461502 Hom.: 0 Cov.: 33 AF XY: 0.0000303 AC XY: 22 AN XY: 727058

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: 2 AN: 152206 Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0 AN XY: 74358

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.: 0

Bravo AF: 0.0000189

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.000116 AC: 1

EpiCase AF: 0.0000545

EpiControl AF: 0.00

ClinVar

Significance: Likely pathogenic

Submissions summary: Pathogenic:14 Other:1

Revision: reviewed by expert panel

Submissions by phenotype

Malignant hyperthermia, susceptibility to, 1 Pathogenic:7

Jul 01, 2013

Biesecker Lab/Clinical Genomics Section, National Institutes of Health

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: research

- -

-

Rady Children's Institute for Genomic Medicine, Rady Children's Hospital San Diego

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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. -

Sep 24, 2024

All of Us Research Program, National Institutes of Health

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.5183C>T (p.Ser1728Phe) variant, located on the exon 34 of the RYR1 gene, replaces arginine with phenylalanine at codon 1728 of the RYR1 protein (p.Ser1728Phe). This missense change has been observed in ten individuals with personal or family histories of malignant hyperthermia reaction, positive in vitro contracture test (IVCT) or caffeine halothane contracture test (CHCT) (PMID:19648156, 30236257, 24195946). This variant has been reported to segregate with malignant hyperthermia susceptibility (MHS) in six unrelated families (PMID:19648156, 30236257). Computational prediction tools do not suggest a strongly deleterious impact on protein structure and function (REVEL score: 0.477). This variant is rare (1/246040 chromosomes) in the general population database by gnomAD. This variant has been classified as likely pathogenic by the expert review panel in ClinVar (ID: 133144). Therefore, the c.5183C>T (p.Ser1728Phe) variant in the RYR1 gene is classified as likely pathogenic. -

Sep 03, 2020

HudsonAlpha Institute for Biotechnology, HudsonAlpha Institute for Biotechnology

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: research

ACMG codes:PS4, PM2, PP3, PP5 -

May 20, 2023

ClinGen Malignant Hyperthermia Susceptibility Variant Curation Expert Panel, ClinGen

Significance: Likely pathogenic

Review Status: reviewed by expert panel

Collection Method: curation

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. -

Aug 06, 2021

National Institute of Allergy and Infectious Diseases - Centralized Sequencing Program, National Institutes of Health

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Jun 01, 2014

CSER _CC_NCGL, University of Washington

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: research

- -

not provided Pathogenic:2 Other:1

-

RYR1 database

Significance: not provided

Review Status: no classification provided

Collection Method: literature only

- -

Sep 20, 2024

GeneDx

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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) -

Sep 22, 2023

Revvity Omics, Revvity

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

RYR1-related disorder Pathogenic:2

Jan 07, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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). 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 not expected to disrupt RYR1 protein function with a negative predictive value of 80%. 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. -

Sep 03, 2024

PreventionGenetics, part of Exact Sciences

Significance: Likely pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

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

Aug 04, 2016

Ambry Genetics

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Malignant hyperthermia of anesthesia Pathogenic:1

Feb 11, 2020

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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;C1840365:King Denborough syndrome;C1850674:Congenital multicore myopathy with external ophthalmoplegia;C2930980:Malignant hyperthermia, susceptibility to, 1;C5830701:Central core myopathy Pathogenic:1

Oct 22, 2021

Fulgent Genetics, Fulgent Genetics

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.49
BayesDel_addAF	Uncertain	0.071	D
BayesDel_noAF	Uncertain	-0.050
CADD	Uncertain	24
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.44	.;T
Eigen	Uncertain	0.28
Eigen_PC	Uncertain	0.26
FATHMM_MKL	Benign	0.34	N
LIST_S2	Benign	0.84	T;T
M_CAP	Uncertain	0.091	D
MetaRNN	Uncertain	0.71	D;D
MetaSVM	Benign	-0.67	T
MutationAssessor	Benign	1.4	L;L
PrimateAI	Uncertain	0.57	T
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	D
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

Other links and lift over

dbSNP: rs193922781; hg19: chr19-38976478;