rs35364374

chr19-38492540-G-T

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.6178G>T(p.Gly2060Cys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0667 in 1,614,032 control chromosomes in the GnomAD database, including 4,446 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★★).

• Frequency:
  • Genomes: 𝑓 0.051 (301 hom., cov: 32)
  • Exomes 𝑓: 0.068 (4145 hom.)
• Consequence: RYR1 NM_000540.3 missense
• Clinical Significance: Benign reviewed by expert panel B:17 O:1
• Conservation: PhyloP100: 0.786

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=0.0020361245).
• BP6: Variant 19-38492540-G-T is Benign according to our data. Variant chr19-38492540-G-T is described in ClinVar as [Benign]. Clinvar id is 93279.Status of the report is reviewed_by_expert_panel, 3 stars. Variant chr19-38492540-G-T is described in Lovd as [Benign]. Variant chr19-38492540-G-T is described in Lovd as [Likely_benign].
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.15 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
RYR1	NM_000540.3	c.6178G>T	p.Gly2060Cys	missense_variant	38/106	ENST00000359596.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
RYR1	ENST00000359596.8	c.6178G>T	p.Gly2060Cys	missense_variant	38/106	5	NM_000540.3	A2
RYR1	ENST00000355481.8	c.6178G>T	p.Gly2060Cys	missense_variant	38/105	1		P4
RYR1	ENST00000599547.6	c.6178G>T	p.Gly2060Cys	missense_variant, NMD_transcript_variant	38/80	2

Frequencies

GnomAD3 genomes AF: 0.0511 AC: 7770 AN: 152108 Hom.: 304 Cov.: 32

Gnomad AFR AF: 0.0125

Gnomad AMI AF: 0.0307

Gnomad AMR AF: 0.0565

Gnomad ASJ AF: 0.0931

Gnomad EAS AF: 0.00443

Gnomad SAS AF: 0.160

Gnomad FIN AF: 0.0174

Gnomad MID AF: 0.120

Gnomad NFE AF: 0.0718

Gnomad OTH AF: 0.0654

GnomAD3 exomes AF: 0.0685 AC: 17228 AN: 251328 Hom.: 897 AF XY: 0.0736 AC XY: 10003 AN XY: 135856

Gnomad AFR exome AF: 0.0106

Gnomad AMR exome AF: 0.0746

Gnomad ASJ exome AF: 0.0820

Gnomad EAS exome AF: 0.00261

Gnomad SAS exome AF: 0.156

Gnomad FIN exome AF: 0.0206

Gnomad NFE exome AF: 0.0698

Gnomad OTH exome AF: 0.0711

GnomAD4 exome AF: 0.0684 AC: 99923 AN: 1461806 Hom.: 4145 Cov.: 34 AF XY: 0.0714 AC XY: 51946 AN XY: 727200

Gnomad4 AFR exome AF: 0.0124

Gnomad4 AMR exome AF: 0.0719

Gnomad4 ASJ exome AF: 0.0869

Gnomad4 EAS exome AF: 0.00647

Gnomad4 SAS exome AF: 0.153

Gnomad4 FIN exome AF: 0.0205

Gnomad4 NFE exome AF: 0.0672

Gnomad4 OTH exome AF: 0.0672

GnomAD4 genome AF: 0.0510 AC: 7768 AN: 152226 Hom.: 301 Cov.: 32 AF XY: 0.0500 AC XY: 3720 AN XY: 74420

Gnomad4 AFR AF: 0.0124

Gnomad4 AMR AF: 0.0566

Gnomad4 ASJ AF: 0.0931

Gnomad4 EAS AF: 0.00444

Gnomad4 SAS AF: 0.160

Gnomad4 FIN AF: 0.0174

Gnomad4 NFE AF: 0.0718

Gnomad4 OTH AF: 0.0666

Alfa AF: 0.0668 Hom.: 533

Bravo AF: 0.0491

TwinsUK AF: 0.0642 AC: 238

ALSPAC AF: 0.0791 AC: 305

ESP6500AA AF: 0.0127 AC: 56

ESP6500EA AF: 0.0713 AC: 613

ExAC AF: 0.0692 AC: 8407

Asia WGS AF: 0.0910 AC: 314 AN: 3478

EpiCase AF: 0.0778

EpiControl AF: 0.0772

ClinVar

Significance: Benign

Submissions summary: Benign:17 Other:1

Revision: reviewed by expert panel

Submissions by phenotype

not specified Benign:7

Benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Jul 31, 2013	- -
Benign, criteria provided, single submitter	clinical testing	Genetic Services Laboratory, University of Chicago	Aug 15, 2013	- -
Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	Mar 21, 2018	- -
Benign, no assertion criteria provided	clinical testing	Clinical Genetics, Academic Medical Center	-	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Feb 08, 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, no assertion criteria provided	clinical testing	Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	-	- -
Benign, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Jan 13, 2015	p.Gly2060Cys in exon 38 of RYR1: This variant is not expected to have clinical s ignificance because it has been identified in 7.1% (613/8600) of European Americ an chromosomes from a broad population by the NHLBI Exome Sequencing Project (ht tp://evs.gs.washington.edu/EVS; dbSNP rs35364374). -

Malignant hyperthermia, susceptibility to, 1 Benign:5

Benign, criteria provided, single submitter	clinical testing	All of Us Research Program, National Institutes of Health	Feb 05, 2024	- -
Benign, criteria provided, single submitter	clinical testing	Color Diagnostics, LLC DBA Color Health	Mar 05, 2018	- -
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 Glycine with Cysteine at codon 2060 of the RYR1 protein, p.(Gly2060Cys). The maximum allele frequency for this variant among the six major gnomAD populations is SAS: 0.1562, 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	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 12, 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:2

Benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Jun 14, 2016	- -
Benign, no assertion criteria provided	curation	GeneReviews	May 11, 2010	- -

Congenital multicore myopathy with external ophthalmoplegia Benign:1

Benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jan 12, 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. -

RYR1-related disorder Benign:1

Benign, criteria provided, single submitter

clinical testing

Invitae

Feb 01, 2024

- -

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

Benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jun 14, 2016

- -

not provided Other:1

not provided, no classification provided

literature only

Leiden Muscular Dystrophy (RYR1)

-

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.22
BayesDel_addAF	Benign	-0.51	T
BayesDel_noAF	Benign	-0.37
Cadd	Benign	22
Dann	Uncertain	0.99
Eigen	Benign	0.16
Eigen_PC	Benign	0.13
FATHMM_MKL	Benign	0.48	N
LIST_S2	Benign	0.67	T;T
MetaRNN	Benign	0.0020	T;T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	1.9	L;L
MutationTaster	Benign	1.0	N;N;N
PrimateAI	Uncertain	0.53	T
PROVEAN	Benign	-2.0	N;N
REVEL	Benign	0.17
Sift	Benign	0.058	T;T
Polyphen		0.97	D;P
Vest4		0.51
MPC		0.46
ClinPred		0.014	T
GERP RS		1.7
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.10
gMVP		0.14

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: rs35364374; hg19: chr19-38983180;