rs143987857

chr19-38525492-G-A

Variant summary

Our verdict is Benign. Variant got -8 ACMG points: 2P and 10B. PP2 PP3 BP4_Moderate BP6_Very_Strong

The NM_000540.3(RYR1):c.10616G>A(p.Arg3539His) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00218 in 1,613,774 control chromosomes in the GnomAD database, including 7 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★★).

• Frequency:
  • Genomes: 𝑓 0.0016 (0 hom., cov: 30)
  • Exomes 𝑓: 0.0022 (7 hom.)
• Consequence: RYR1 NM_000540.3 missense
• Clinical Significance: Likely benign reviewed by expert panel U:15 B:9 O:2
• Conservation: PhyloP100: 9.76

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 -8 ACMG points.

• PP2: Missense variant where missense usually causes diseases, RYR1
• PP3: Multiple lines of computational evidence support a deleterious effect 7: AlphaMissense, BayesDel_noAF, Eigen, M_CAP, phyloP100way_vertebrate, PROVEAN, REVEL [when FATHMM_MKL, MetaRNN, MutationTaster was below the threshold]
• BP4: Computational evidence support a benign effect (MetaRNN=0.090333015).
• BP6: Variant 19-38525492-G-A is Benign according to our data. Variant chr19-38525492-G-A is described in ClinVar as [Likely_benign]. Clinvar id is 132997.Status of the report is reviewed_by_expert_panel, 3 stars. Variant chr19-38525492-G-A is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
RYR1	NM_000540.3	c.10616G>A	p.Arg3539His	missense_variant	71/106	ENST00000359596.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
RYR1	ENST00000359596.8	c.10616G>A	p.Arg3539His	missense_variant	71/106	5	NM_000540.3	A2
RYR1	ENST00000355481.8	c.10601G>A	p.Arg3534His	missense_variant	70/105	1		P4
RYR1	ENST00000594335.5	c.*1344G>A		3_prime_UTR_variant, NMD_transcript_variant	30/49	1
RYR1	ENST00000599547.6	c.*1375G>A		3_prime_UTR_variant, NMD_transcript_variant	70/80	2

Frequencies

GnomAD3 genomes AF: 0.00165 AC: 251 AN: 151956 Hom.: 0 Cov.: 30

Gnomad AFR AF: 0.000556

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000262

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000416

Gnomad FIN AF: 0.00104

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00306

Gnomad OTH AF: 0.00144

GnomAD3 exomes AF: 0.00155 AC: 389 AN: 250486 Hom.: 1 AF XY: 0.00174 AC XY: 236 AN XY: 135588

Gnomad AFR exome AF: 0.000495

Gnomad AMR exome AF: 0.0000869

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.000653

Gnomad FIN exome AF: 0.00102

Gnomad NFE exome AF: 0.00293

Gnomad OTH exome AF: 0.000817

GnomAD4 exome AF: 0.00224 AC: 3271 AN: 1461700 Hom.: 7 Cov.: 32 AF XY: 0.00215 AC XY: 1567 AN XY: 727156

Gnomad4 AFR exome AF: 0.000388

Gnomad4 AMR exome AF: 0.000179

Gnomad4 ASJ exome AF: 0.0000383

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.000522

Gnomad4 FIN exome AF: 0.000880

Gnomad4 NFE exome AF: 0.00273

Gnomad4 OTH exome AF: 0.00194

GnomAD4 genome AF: 0.00164 AC: 250 AN: 152074 Hom.: 0 Cov.: 30 AF XY: 0.00164 AC XY: 122 AN XY: 74344

Gnomad4 AFR AF: 0.000555

Gnomad4 AMR AF: 0.000262

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000208

Gnomad4 FIN AF: 0.00104

Gnomad4 NFE AF: 0.00306

Gnomad4 OTH AF: 0.00142

Alfa AF: 0.00240 Hom.: 0

Bravo AF: 0.00144

TwinsUK AF: 0.00189 AC: 7

ALSPAC AF: 0.00467 AC: 18

ESP6500AA AF: 0.000681 AC: 3

ESP6500EA AF: 0.00244 AC: 21

ExAC AF: 0.00173 AC: 210

Asia WGS AF: 0.000577 AC: 2 AN: 3478

EpiCase AF: 0.00245

EpiControl AF: 0.00213

ClinVar

Significance: Likely benign

Submissions summary: Uncertain:15 Benign:9 Other:2

Revision: reviewed by expert panel

Submissions by phenotype

not provided Uncertain:11 Benign:3 Other:1

Uncertain significance, no assertion criteria provided	clinical testing	Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)	-	- -
Uncertain significance, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	May 25, 2016	- -
not provided, no classification provided	literature only	Leiden Muscular Dystrophy (RYR1)	-	- -
Uncertain significance, no assertion criteria provided	clinical testing	Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	-	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Aug 01, 2016	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Mayo Clinic Laboratories, Mayo Clinic	Jun 03, 2021	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Athena Diagnostics	Jun 22, 2021	- -
Likely benign, criteria provided, single submitter	clinical testing	GeneDx	Aug 16, 2021	See Variant Classification Assertion Criteria. -
Uncertain significance, no assertion criteria provided	clinical testing	Department of Pathology and Laboratory Medicine, Sinai Health System	-	- -
Likely benign, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Nov 07, 2023	- -
Uncertain significance, no assertion criteria provided	clinical testing	Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	-	- -
Uncertain significance, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, Amsterdam University Medical Center	-	- -
Uncertain significance, no assertion criteria provided	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	-	- -
Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Mar 01, 2024	RYR1: BS1 -
Uncertain significance, criteria provided, single submitter	clinical testing	Revvity Omics, Revvity	Sep 15, 2023	- -

not specified Uncertain:3 Benign:1

Uncertain significance, criteria provided, single submitter	clinical testing	Genomic Diagnostic Laboratory, Division of Genomic Diagnostics, Children's Hospital of Philadelphia	Jun 18, 2015	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Genetic Services Laboratory, University of Chicago	Feb 02, 2017	- -
Likely benign, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Jan 07, 2022	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Jan 24, 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 classified in HGMD as DM relating to central core disease and is reported in 10 papers, with comments suggesting VUS/LB. This variant has a Max MAF of 0.30% in ExAC (384/126200 European chrs including 1 homozygote - high for central core disease prevalence of 6/100,000). It is classified in ClinVar as VUS by 4 submitters (Emory, GeneDx, CHOP, Biesecker), and Likely benign by U Wash. -

Malignant hyperthermia, susceptibility to, 1 Uncertain:1 Benign:2

Uncertain significance, criteria provided, single submitter	research	Biesecker Lab/Clinical Genomics Section, National Institutes of Health	Jul 01, 2013	- -
Benign, criteria provided, single submitter	clinical testing	Mendelics	May 28, 2019	- -
Likely benign, criteria provided, single submitter	clinical testing	Color Diagnostics, LLC DBA Color Health	Aug 18, 2022	- -

RYR1-Related Disorders Benign:1 Other:1

not provided, no classification provided	phenotyping only	GenomeConnect, ClinGen	-	Variant interpreted as Uncertain significance and reported on 05-17-2017 by Lab or GTR ID 303161. GenomeConnect assertions are reported exactly as they appear on the patient-provided report from the testing laboratory. GenomeConnect staff make no attempt to reinterpret the clinical significance of the variant. -
Likely benign, criteria provided, single submitter	clinical testing	Invitae	Jan 29, 2024	- -

Central core myopathy Benign:1

Likely benign, no assertion criteria provided

research

CSER _CC_NCGL, University of Washington

Jun 01, 2014

- -

Malignant hyperthermia of anesthesia Benign:1

Likely benign, reviewed by expert panel

curation

ClinGen Malignant Hyperthermia Susceptibility Variant Curation Expert Panel, ClinGen

Nov 10, 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 arginine with histidine at codon 3539 of the RYR1 protein, p.(Arg3539His). The maximum allele frequency for this variant among the six major gnomAD populations is NFE: 0.00305, this is considered to be more common than expected for a pathogenic variant causing autosomal dominantly inherited MHS, BS1. This variant has been reported in 10 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 (if the proband was unavailable for testing, a positive diagnostic test result in a mutation-positive relative was counted) (PMID:30236257; PMID:23460944; PMID:23558838; PMID:24433488; PMID:25960145), however, the high MAF in the NFE population precludes the use of PS4. This variant has been identified in multiple individuals with negative IVCT/CHCT results, BS2 (PMID:18253926, PMID:22473935). 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 (0.877) supports a pathogenic status for this variant, PP3_Moderate. Based on using Bayes to combine criteria this variant is assessed as Likely Benign, (PMID: 29300386). Criteria implemented: PP3_Moderate, BS1, BS2. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.59
BayesDel_addAF	Uncertain	0.047	T
BayesDel_noAF	Pathogenic	0.30
Cadd	Uncertain	25
Dann	Uncertain	0.99
Eigen	Pathogenic	0.72
Eigen_PC	Uncertain	0.62
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Uncertain	0.97	D;D
M_CAP	Pathogenic	0.38	D
MetaRNN	Benign	0.090	T;T
MetaSVM	Pathogenic	1.1	D
MutationTaster	Benign	1.0	D;D;D
PrimateAI	Uncertain	0.62	T
PROVEAN	Pathogenic	-4.4	D;D
REVEL	Pathogenic	0.88
Sift	Uncertain	0.0020	D;D
Polyphen		1.0	D;D
Vest4		0.71
MVP		0.98
MPC		0.38
ClinPred		0.059	T
GERP RS		3.1
Varity_R		0.41
gMVP		0.50

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: rs143987857; hg19: chr19-39016132; COSMIC: COSV62094702; COSMIC: COSV62094702;