rs34390345

Positions:

• chr19-38499177-A-G
• chr19-38499177-A-T

Variant summary

Our verdict is Benign. Variant got -7 ACMG points: 2P and 9B. PM1 BS3_Supporting BS1 BS2

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 isoleucine with valine at codon 2321 of the RYR1 protein p.(Ile2321Val). The maximum allele frequency for this variant among the six major gnomAD populations is NFE: 0.00081, this is considered to be more common than expected for a pathogenic variant causing autosomal dominant MHS, BS1. This variant has been reported in four unrelated individuals who have a personal or family history of a malignant hyperthermia reaction, all of these individuals had a positive in vitro contracture test (IVCT) or caffeine halothane contracture test (CHCT) result (when the proband was unavailable for testing a positive diagnostic test result in a mutation positive relative was counted) (PMID:30236257; PMID:23558838). However, the high MAF in the NFE population in gnomAD precludes the use of PS4. This variant has been identified in families with genotype positive/ phenotype negative individuals (IVCT) supporting a benign status, BS2 (PMID:30236257, personal communications). Variant did not show increased sensitivity to RYR1 agonists in HEK293 assay (personal communication), BS3_Supporting. This variant resides in a region of RYR1 considered to be a hotspot for pathogenic variants that contribute to MHS, PM1 (PMID:21118704). A REVEL score of 0.712 does not support pathogenic or a benign status. This variant has been classified as Benign. Criteria implemented: BS1, BS2, BS3_Supporting, PM1. LINK:https://erepo.genome.network/evrepo/ui/classification/CA024659/MONDO:0007783/012

• Frequency:
  • Genomes: 𝑓 0.00056 (0 hom., cov: 32)
  • Exomes 𝑓: 0.0012 (0 hom.)
• Consequence: RYR1 NM_000540.3 missense
• Clinical Significance: Benign reviewed by expert panel U:7 B:11 O:1
• Conservation: PhyloP100: 6.18

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 Benign. Variant got -7 ACMG points.

• PM1: For more information check the summary or visit ClinGen Evidence Repository.
• BS1: For more information check the summary or visit ClinGen Evidence Repository.
• BS2: For more information check the summary or visit ClinGen Evidence Repository.
• BS3: 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.6961A>G	p.Ile2321Val	missense_variant	43/106	ENST00000359596.8	NP_000531.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
RYR1	ENST00000359596.8	c.6961A>G	p.Ile2321Val	missense_variant	43/106	5	NM_000540.3	ENSP00000352608	A2
RYR1	ENST00000355481.8	c.6961A>G	p.Ile2321Val	missense_variant	43/105	1		ENSP00000347667	P4
RYR1	ENST00000594335.5	c.415A>G	p.Ile139Val	missense_variant, NMD_transcript_variant	4/49	1		ENSP00000470927
RYR1	ENST00000599547.6	c.6961A>G	p.Ile2321Val	missense_variant, NMD_transcript_variant	43/80	2		ENSP00000471601

Frequencies

GnomAD3 genomes AF: 0.000565 AC: 86 AN: 152190 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.000290

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0000655

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.000188

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00103

Gnomad OTH AF: 0.000478

GnomAD3 exomes AF: 0.000442 AC: 111 AN: 251396 Hom.: 0 AF XY: 0.000464 AC XY: 63 AN XY: 135898

Gnomad AFR exome AF: 0.000492

Gnomad AMR exome AF: 0.000260

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.000139

Gnomad NFE exome AF: 0.000800

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00123 AC: 1804 AN: 1461880 Hom.: 0 Cov.: 32 AF XY: 0.00120 AC XY: 874 AN XY: 727246

Gnomad4 AFR exome AF: 0.000358

Gnomad4 AMR exome AF: 0.000291

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.0000936

Gnomad4 NFE exome AF: 0.00155

Gnomad4 OTH exome AF: 0.000878

GnomAD4 genome AF: 0.000565 AC: 86 AN: 152308 Hom.: 0 Cov.: 32 AF XY: 0.000456 AC XY: 34 AN XY: 74486

Gnomad4 AFR AF: 0.000289

Gnomad4 AMR AF: 0.0000654

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.000188

Gnomad4 NFE AF: 0.00103

Gnomad4 OTH AF: 0.000473

Alfa AF: 0.000918 Hom.: 0

Bravo AF: 0.000638

TwinsUK AF: 0.00108 AC: 4

ALSPAC AF: 0.00234 AC: 9

ESP6500AA AF: 0.000227 AC: 1

ESP6500EA AF: 0.00116 AC: 10

ExAC AF: 0.000387 AC: 47

EpiCase AF: 0.00120

EpiControl AF: 0.00130

ClinVar

Significance: Benign

Submissions summary: Uncertain:7 Benign:11 Other:1

Revision: reviewed by expert panel

Submissions by phenotype

not provided Uncertain:5 Benign:1 Other:1

Uncertain significance, criteria provided, single submitter	clinical testing	Revvity Omics, Revvity	Aug 09, 2023	- -
not provided, no classification provided	literature only	Leiden Muscular Dystrophy (RYR1)	-	- -
Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Apr 01, 2024	RYR1: BS1 -
Uncertain significance, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	Dec 12, 2017	- -
Uncertain significance, no assertion criteria provided	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	-	- -
Uncertain significance, no assertion criteria provided	clinical testing	Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	-	- -
Uncertain significance, criteria provided, single submitter	clinical testing	GeneDx	Jun 10, 2024	Identified in patients with malignant hyperthermia; however, additional clinical information was not provided and functional characterization of the variant was not completed (PMID: 16917943, 30236257); Also reported as a polymorphism (PMID: 19191329, 23558838, 24195946); In silico analysis indicates that this missense variant does not alter protein structure/function; This variant is associated with the following publications: (PMID: 24948473, 26972305, 24195946, 26332594, 23558838, 27377473, 20301325, 24055113, 25637381, 30788618, 30236257, 27663056, 34348614, 36208971, 37937776, 12668474, 33767344, 19191329, 16917943) -

Malignant hyperthermia, susceptibility to, 1 Uncertain:1 Benign:4

Likely benign, criteria provided, single submitter	clinical testing	Color Diagnostics, LLC DBA Color Health	Jul 13, 2022	- -
Uncertain significance, no assertion criteria provided	research	CSER _CC_NCGL, University of Washington	Jun 01, 2014	- -
Likely benign, criteria provided, single submitter	research	Biesecker Lab/Clinical Genomics Section, National Institutes of Health	Jul 01, 2013	- -
Benign, reviewed by expert panel	curation	ClinGen Malignant Hyperthermia Susceptibility Variant Curation Expert Panel, ClinGen	Mar 18, 2021	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 isoleucine with valine at codon 2321 of the RYR1 protein p.(Ile2321Val). The maximum allele frequency for this variant among the six major gnomAD populations is NFE: 0.00081, this is considered to be more common than expected for a pathogenic variant causing autosomal dominant MHS, BS1. This variant has been reported in four unrelated individuals who have a personal or family history of a malignant hyperthermia reaction, all of these individuals had a positive in vitro contracture test (IVCT) or caffeine halothane contracture test (CHCT) result (when the proband was unavailable for testing a positive diagnostic test result in a mutation positive relative was counted) (PMID:30236257; PMID:23558838). However, the high MAF in the NFE population in gnomAD precludes the use of PS4. This variant has been identified in families with genotype positive/ phenotype negative individuals (IVCT) supporting a benign status, BS2 (PMID:30236257, personal communications). Variant did not show increased sensitivity to RYR1 agonists in HEK293 assay (personal communication), BS3_Supporting. This variant resides in a region of RYR1 considered to be a hotspot for pathogenic variants that contribute to MHS, PM1 (PMID: 21118704). A REVEL score of 0.712 does not support pathogenic or a benign status. This variant has been classified as Benign. Criteria implemented: BS1, BS2, BS3_Supporting, PM1. -
Likely benign, 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). Publications were found based on this search. The evidence from the literature, in combination with allele frequency data from public databases where available, was sufficient to determine this variant is unlikely to cause disease. Therefore, this variant is classified as likely benign. -

not specified Uncertain:1 Benign:1

Uncertain significance, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Feb 03, 2017	Variant identified in a genome or exome case(s) and assessed due to predicted null impact of the variant or pathogenic assertions in the literature or databases. Disclaimer: This variant has not undergone full assessment. The following are preliminary notes: This variant is present in HGMD in 5 papers but classified as VUS. Comments: Variant found in 1/870 ClinSeq participants not selected for malignant hyperthermia susceptibility (24195946); Co-occurred with another variant in RYR1 in a family with MHS (19191329). It is classified in ClinVar with 1 star as Likelybenign by Biesecker and VUS by CSER. It has a max MAF in ExAC of 0.06% (41 alleles) and in gnomAD of 0.08% (101 alleles). Frequency too high for disease - MHS prevalence is estimated at max 1/5000. -
Likely benign, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Jun 12, 2024	Variant summary: RYR1 c.6961A>G (p.Ile2321Val) results in a conservative amino acid change located in the RIH domain (IPR000699) of the encoded protein sequence. Three of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 0.00044 in 251396 control chromosomes. The observed variant frequency is approximately 5-fold of the estimated maximal expected allele frequency for a pathogenic variant in RYR1 causing Malignant Hyperthermia Susceptibility phenotype (8.8e-05). c.6961A>G has been reported in the literature in individuals affected with Malignant Hyperthermia Susceptibility without strong evidence for causality (such as segregation) (examples: Brandom_2013, Miller_2018, Levano_2009, Lopez_2016, Jensson_2023). The variant has also been reported to co-occur with other pathogenic variants (RYR1: c.14545G>A, c.38T>G) (Levano_2009, Lopez_2016.). At least one publication reports experimental evidence evaluating an impact on protein function. These results showed no damaging effect of this variant (White_2022). The following publications have been ascertained in the context of this evaluation (PMID: 30236257, 37937776, 19191329, 27382027, 36208971, 23558838). ClinVar contains an entry for this variant (Variation ID: 133173). Based on the evidence outlined above, the variant was classified as likely benign. -

Congenital multicore myopathy with external ophthalmoplegia Benign:1

Likely benign, 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 allowed determination this variant is unlikely to cause disease. Therefore, this variant is classified as likely benign. -

Central core myopathy Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jun 14, 2016

- -

RYR1-related disorder Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Jan 25, 2024

- -

Neuromuscular disease, congenital, with uniform type 1 fiber Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jun 14, 2016

- -

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 Benign:1

Benign, criteria provided, single submitter

clinical testing

Fulgent Genetics, Fulgent Genetics

Oct 10, 2021

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.099
BayesDel_addAF	Benign	-0.039	T
BayesDel_noAF	Pathogenic	0.17
CADD	Benign	21
DANN	Benign	0.76
DEOGEN2	Uncertain	0.63	.;D
Eigen	Uncertain	0.34
Eigen_PC	Uncertain	0.28
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Benign	0.81	T;T
M_CAP	Uncertain	0.087	D
MetaRNN	Benign	0.24	T;T
MetaSVM	Pathogenic	0.86	D
MutationAssessor	Benign	1.8	L;L
MutationTaster	Benign	0.99	D;D;D
PrimateAI	Uncertain	0.65	T
PROVEAN	Benign	-0.69	N;N
REVEL	Pathogenic	0.71
Sift	Benign	0.16	T;T
Polyphen		0.88	P;P
Vest4		0.50
MVP		0.98
MPC		0.27
ClinPred		0.11	T
GERP RS		4.1
Varity_R		0.079
gMVP		0.62

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: rs34390345; hg19: chr19-38989817;