rs4802584

chr19-38534726-C-G

Variant summary

Our verdict is Benign. Variant got -19 ACMG points: 1P and 20B. PP2 BP4_Strong BP6_Very_Strong BA1

The NM_000540.3(RYR1):c.11266C>G(p.Gln3756Glu) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0228 in 1,613,680 control chromosomes in the GnomAD database, including 822 homozygotes. In-silico tool predicts a benign outcome for this variant. 11/19 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★★).

• Frequency:
  • Genomes: 𝑓 0.023 (93 hom., cov: 31)
  • Exomes 𝑓: 0.023 (729 hom.)
• Consequence: RYR1 NM_000540.3 missense
• Clinical Significance: Benign reviewed by expert panel B:17 O:1
• Conservation: PhyloP100: 8.16

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 -19 ACMG points.

• PP2: Missense variant where missense usually causes diseases, RYR1
• BP4: Computational evidence support a benign effect (MetaRNN=0.0013844073).
• BP6: Variant 19-38534726-C-G is Benign according to our data. Variant chr19-38534726-C-G is described in ClinVar as [Benign]. Clinvar id is 133011.Status of the report is reviewed_by_expert_panel, 3 stars. Variant chr19-38534726-C-G is described in Lovd as [Likely_benign]. Variant chr19-38534726-C-G is described in Lovd as [Benign]. Variant chr19-38534726-C-G is described in Lovd as [Pathogenic].
• BA1: GnomAd4 highest subpopulation (AMR) allele frequency at 95% confidence interval = 0.0692 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
RYR1	NM_000540.3	c.11266C>G	p.Gln3756Glu	missense_variant	79/106	ENST00000359596.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
RYR1	ENST00000359596.8	c.11266C>G	p.Gln3756Glu	missense_variant	79/106	5	NM_000540.3	A2

Frequencies

GnomAD3 genomes AF: 0.0227 AC: 3452 AN: 152162 Hom.: 92 Cov.: 31

Gnomad AFR AF: 0.00777

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0725

Gnomad ASJ AF: 0.00173

Gnomad EAS AF: 0.0596

Gnomad SAS AF: 0.0327

Gnomad FIN AF: 0.0445

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.0151

Gnomad OTH AF: 0.0239

GnomAD3 exomes AF: 0.0345 AC: 8651 AN: 250408 Hom.: 300 AF XY: 0.0318 AC XY: 4311 AN XY: 135396

Gnomad AFR exome AF: 0.00730

Gnomad AMR exome AF: 0.109

Gnomad ASJ exome AF: 0.00209

Gnomad EAS exome AF: 0.0475

Gnomad SAS exome AF: 0.0302

Gnomad FIN exome AF: 0.0448

Gnomad NFE exome AF: 0.0163

Gnomad OTH exome AF: 0.0280

GnomAD4 exome AF: 0.0228 AC: 33386 AN: 1461400 Hom.: 729 Cov.: 32 AF XY: 0.0226 AC XY: 16409 AN XY: 726938

Gnomad4 AFR exome AF: 0.00633

Gnomad4 AMR exome AF: 0.108

Gnomad4 ASJ exome AF: 0.00226

Gnomad4 EAS exome AF: 0.0686

Gnomad4 SAS exome AF: 0.0286

Gnomad4 FIN exome AF: 0.0442

Gnomad4 NFE exome AF: 0.0172

Gnomad4 OTH exome AF: 0.0258

GnomAD4 genome AF: 0.0227 AC: 3455 AN: 152280 Hom.: 93 Cov.: 31 AF XY: 0.0254 AC XY: 1891 AN XY: 74452

Gnomad4 AFR AF: 0.00772

Gnomad4 AMR AF: 0.0728

Gnomad4 ASJ AF: 0.00173

Gnomad4 EAS AF: 0.0596

Gnomad4 SAS AF: 0.0327

Gnomad4 FIN AF: 0.0445

Gnomad4 NFE AF: 0.0151

Gnomad4 OTH AF: 0.0237

Alfa AF: 0.0178 Hom.: 34

Bravo AF: 0.0239

TwinsUK AF: 0.0189 AC: 70

ALSPAC AF: 0.0202 AC: 78

ESP6500AA AF: 0.00590 AC: 26

ESP6500EA AF: 0.0149 AC: 128

ExAC AF: 0.0314 AC: 3818

Asia WGS AF: 0.0570 AC: 198 AN: 3478

EpiCase AF: 0.0130

EpiControl AF: 0.0138

ClinVar

Significance: Benign

Submissions summary: Benign:17 Other:1

Revision: reviewed by expert panel

Submissions by phenotype

not specified Benign:6

Benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Apr 22, 2014	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Feb 17, 2016	This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. -
Benign, criteria provided, single submitter	clinical testing	Athena Diagnostics	Dec 02, 2019	- -
Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	Mar 06, 2018	- -
Benign, criteria provided, single submitter	clinical testing	Genetic Services Laboratory, University of Chicago	Feb 08, 2013	- -
Benign, no assertion criteria provided	clinical testing	Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	-	- -

Malignant hyperthermia, susceptibility to, 1 Benign:5

Benign, criteria provided, single submitter	clinical testing	Color Diagnostics, LLC DBA Color Health	Mar 05, 2018	- -
Benign, criteria provided, single submitter	research	Biesecker Lab/Clinical Genomics Section, National Institutes of Health	Jul 01, 2013	- -
Benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Jan 13, 2018	This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -
Benign, reviewed by expert panel	curation	ClinGen Malignant Hyperthermia Susceptibility Variant Curation Expert Panel, ClinGen	Mar 17, 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 Glutamine with Glutamic Acid at codon 3756 of the RYR1 protein, p.(Gln3756Glu). The maximum allele frequency for this variant among the six major gnomAD populations is AMR: 0.1085, which is considered to be too common for a pathogenic variant causing autosomal dominantly inherited MHS, BA1. This variant has been classified as Benign. Criteria implemented: BA1. -
Benign, criteria provided, single submitter	clinical testing	All of Us Research Program, National Institutes of Health	Feb 05, 2024	- -

not provided Benign:2 Other:1

not provided, no classification provided	literature only	Leiden Muscular Dystrophy (RYR1)	-	- -
Likely benign, no assertion criteria provided	clinical testing	Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)	-	- -
Likely benign, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, University Medical Center Utrecht	-	- -

Congenital multicore myopathy with external ophthalmoplegia Benign:1

Benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jan 13, 2018

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -

Central core myopathy Benign:1

Benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jun 14, 2016

- -

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

Benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jun 14, 2016

- -

RYR1-Related Disorders Benign:1

Benign, criteria provided, single submitter

clinical testing

Invitae

Jan 31, 2024

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.0052
BayesDel_addAF	Benign	-0.54	T
BayesDel_noAF	Benign	-0.47
Cadd	Benign	21
Dann	Benign	0.96
Eigen	Benign	-0.82
Eigen_PC	Benign	-0.48
FATHMM_MKL	Benign	0.062	N
LIST_S2	Benign	0.69	T;T;T
MetaRNN	Benign	0.0014	T;T;T
MetaSVM	Benign	-0.98	T
MutationTaster	Benign	1.0	N;N;N
PrimateAI	Uncertain	0.64	T
PROVEAN	Benign	2.4	N;N;.
REVEL	Uncertain	0.33
Sift	Benign	1.0	T;T;.
Polyphen		0.0	B;B;.
Vest4		0.058
MPC		0.62
ClinPred		0.015	T
GERP RS		4.8
Varity_R		0.054
gMVP		0.074

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.080		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: rs4802584; hg19: chr19-39025366; COSMIC: COSV62093128; COSMIC: COSV62093128;