rs193922844

Positions:

• chr19-38548287-C-A

Variant summary

Our verdict is Likely pathogenic. Variant got 8 ACMG points: 8P and 0B. PS4_Moderate PP1_Strong PP3_Moderate

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 tyrosine at codon 4050 of the RYR1 protein, p.(Ser4050Tyr). This variant was not present in a large population database (gnomAD) at the time this variant was interpreted. This variant has been reported in two unrelated individuals who have a personal or family history of a malignant hyperthermia reaction, both 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_Moderate (PMID:30236257). Two families have been found to segregate this variant in a total of 10 affected individuals (MHS-VCEP laboratory), PP1_Strong. 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 >0.85 (0.942) supports a pathogenic status for this variant, PP3_Moderate. This variant has been classified as a Variant of Unknown Significance. Criteria implemented: PS4_Moderate, PP1_Strong, PP3_Moderate. LINK:https://erepo.genome.network/evrepo/ui/classification/CA023971/MONDO:0007783/012

• Frequency:
  • Genomes: not found (cov: 31)
  • Exomes 𝑓: 0.0000055 (0 hom.)
• Consequence: RYR1 NM_000540.3 missense
• Clinical Significance: Likely pathogenic reviewed by expert panel P:4 O:1
• Conservation: PhyloP100: 7.87

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 8 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.
• PP3: 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	c.12149C>A	p.Ser4050Tyr	missense_variant	89/106	ENST00000359596.8	NP_000531.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
RYR1	ENST00000359596.8	c.12149C>A	p.Ser4050Tyr	missense_variant	89/106	5	NM_000540.3	ENSP00000352608.2

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome AF: 0.00000547 AC: 8 AN: 1461890 Hom.: 0 Cov.: 32 AF XY: 0.00000550 AC XY: 4 AN XY: 727248

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

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: 0.00000719

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 31

EpiCase AF: 0.0000545

EpiControl AF: 0.00

ClinVar

Significance: Likely pathogenic

Submissions summary: Pathogenic:4 Other:1

Revision: reviewed by expert panel

Submissions by phenotype

not provided Pathogenic:2 Other:1

Likely pathogenic, criteria provided, single submitter	clinical testing	Revvity Omics, Revvity	Feb 08, 2023	- -
not provided, no classification provided	literature only	Leiden Muscular Dystrophy (RYR1)	-	- -
Likely pathogenic, criteria provided, single submitter	clinical testing	GeneDx	May 24, 2022	Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 16917943, 30236257) -

Malignant hyperthermia, susceptibility to, 1 Pathogenic:1

Likely pathogenic, reviewed by expert panel

curation

ClinGen Malignant Hyperthermia Susceptibility Variant Curation Expert Panel, ClinGen

Apr 07, 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 tyrosine at codon 4050 of the RYR1 protein, p.(Ser4050Tyr). This variant was not present in a large population database (gnomAD) at the time this variant was interpreted. This variant has been reported in two unrelated individuals who have a personal or family history of a malignant hyperthermia reaction, both 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_Moderate (PMID:30236257). Two families have been found to segregate this variant in a total of 10 affected individuals (MHS-VCEP laboratory), PP1_Strong. 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 >0.85 (0.942) supports a pathogenic status for this variant, PP3_Moderate. This variant has been classified as a Variant of Unknown Significance. Criteria implemented: PS4_Moderate, PP1_Strong, PP3_Moderate. -

RYR1-related disorder Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Mar 14, 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) performed at Invitae indicates that this missense variant is expected to disrupt RYR1 protein function. ClinVar contains an entry for this variant (Variation ID: 133033). This missense change has been observed in individual(s) with malignant hyperthermia susceptibility (PMID: 30236257). This variant is not present in population databases (gnomAD no frequency). This sequence change replaces serine, which is neutral and polar, with tyrosine, which is neutral and polar, at codon 4050 of the RYR1 protein (p.Ser4050Tyr). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.98
BayesDel_addAF	Pathogenic	0.50	D
BayesDel_noAF	Pathogenic	0.48
CADD	Uncertain	23
DANN	Benign	0.88
DEOGEN2	Pathogenic	0.86	.;D
Eigen	Pathogenic	0.77
Eigen_PC	Pathogenic	0.69
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Pathogenic	1.0	D;D
M_CAP	Pathogenic	0.73	D
MetaRNN	Pathogenic	0.96	D;D
MetaSVM	Pathogenic	1.1	D
MutationAssessor	Uncertain	2.8	.;M
PrimateAI	Pathogenic	0.85	D
PROVEAN	Pathogenic	-5.2	D;D
REVEL	Pathogenic	0.94
Sift	Pathogenic	0.0	D;D
Polyphen		1.0	D;D
Vest4		0.77
MutPred		0.78		.;Loss of disorder (P = 0.0129);
MVP		1.0
MPC		0.74
ClinPred		0.99	D
GERP RS		4.5
Varity_R		0.78
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

Other links and lift over

dbSNP: rs193922844; hg19: chr19-39038927;