rs34934920

chr19-38486015-C-T

Variant summary

Our verdict is Benign. Variant got -19 ACMG points: 1P and 20B. PP2 BP4_Strong BP6_Very_Strong BS1 BS2

The NM_000540.3(RYR1):c.5360C>T(p.Pro1787Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0229 in 1,613,524 control chromosomes in the GnomAD database, including 550 homozygotes. In-silico tool predicts a benign outcome for this variant. 12/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★★).

• Frequency:
  • Genomes: 𝑓 0.017 (48 hom., cov: 32)
  • Exomes 𝑓: 0.023 (502 hom.)
• Consequence: RYR1 NM_000540.3 missense
• Clinical Significance: Benign reviewed by expert panel B:20 O:1
• Conservation: PhyloP100: 0.765

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=0.0030625463).
• BP6: Variant 19-38486015-C-T is Benign according to our data. Variant chr19-38486015-C-T is described in ClinVar as [Benign]. Clinvar id is 133149.Status of the report is reviewed_by_expert_panel, 3 stars. Variant chr19-38486015-C-T is described in Lovd as [Benign]. Variant chr19-38486015-C-T is described in Lovd as [Likely_benign].
• BS1: Variant frequency is greater than expected in population sas. gnomad4 allele frequency = 0.0169 (2569/152348) while in subpopulation SAS AF= 0.0479 (231/4826). AF 95% confidence interval is 0.0428. There are 48 homozygotes in gnomad4. There are 1235 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd at 49 AD,AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
RYR1	NM_000540.3	c.5360C>T	p.Pro1787Leu	missense_variant	34/106	ENST00000359596.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
RYR1	ENST00000359596.8	c.5360C>T	p.Pro1787Leu	missense_variant	34/106	5	NM_000540.3	A2
RYR1	ENST00000355481.8	c.5360C>T	p.Pro1787Leu	missense_variant	34/105	1		P4
RYR1	ENST00000599547.6	c.5360C>T	p.Pro1787Leu	missense_variant, NMD_transcript_variant	34/80	2

Frequencies

GnomAD3 genomes AF: 0.0169 AC: 2572 AN: 152230 Hom.: 49 Cov.: 32

Gnomad AFR AF: 0.00461

Gnomad AMI AF: 0.0263

Gnomad AMR AF: 0.0175

Gnomad ASJ AF: 0.0277

Gnomad EAS AF: 0.000192

Gnomad SAS AF: 0.0484

Gnomad FIN AF: 0.00612

Gnomad MID AF: 0.0475

Gnomad NFE AF: 0.0240

Gnomad OTH AF: 0.0215

GnomAD3 exomes AF: 0.0195 AC: 4749 AN: 243108 Hom.: 92 AF XY: 0.0214 AC XY: 2830 AN XY: 132188

Gnomad AFR exome AF: 0.00337

Gnomad AMR exome AF: 0.0120

Gnomad ASJ exome AF: 0.0252

Gnomad EAS exome AF: 0.000165

Gnomad SAS exome AF: 0.0413

Gnomad FIN exome AF: 0.00671

Gnomad NFE exome AF: 0.0232

Gnomad OTH exome AF: 0.0237

GnomAD4 exome AF: 0.0235 AC: 34311 AN: 1461176 Hom.: 502 Cov.: 33 AF XY: 0.0242 AC XY: 17599 AN XY: 726918

Gnomad4 AFR exome AF: 0.00415

Gnomad4 AMR exome AF: 0.0134

Gnomad4 ASJ exome AF: 0.0263

Gnomad4 EAS exome AF: 0.000302

Gnomad4 SAS exome AF: 0.0421

Gnomad4 FIN exome AF: 0.00646

Gnomad4 NFE exome AF: 0.0246

Gnomad4 OTH exome AF: 0.0223

GnomAD4 genome AF: 0.0169 AC: 2569 AN: 152348 Hom.: 48 Cov.: 32 AF XY: 0.0166 AC XY: 1235 AN XY: 74498

Gnomad4 AFR AF: 0.00459

Gnomad4 AMR AF: 0.0175

Gnomad4 ASJ AF: 0.0277

Gnomad4 EAS AF: 0.000193

Gnomad4 SAS AF: 0.0479

Gnomad4 FIN AF: 0.00612

Gnomad4 NFE AF: 0.0240

Gnomad4 OTH AF: 0.0213

Alfa AF: 0.0229 Hom.: 63

Bravo AF: 0.0164

TwinsUK AF: 0.0289 AC: 107

ALSPAC AF: 0.0306 AC: 118

ESP6500AA AF: 0.00409 AC: 18

ESP6500EA AF: 0.0232 AC: 199

ExAC AF: 0.0191 AC: 2315

Asia WGS AF: 0.0130 AC: 46 AN: 3478

EpiCase AF: 0.0281

EpiControl AF: 0.0259

ClinVar

Significance: Benign

Submissions summary: Benign:20 Other:1

Revision: reviewed by expert panel

Submissions by phenotype

not specified Benign:6

Benign, criteria provided, single submitter	clinical testing	Genetic Services Laboratory, University of Chicago	Feb 08, 2013	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Mar 04, 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	PreventionGenetics, part of Exact Sciences	Mar 21, 2018	- -
Benign, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, University Medical Center Utrecht	-	- -
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	Athena Diagnostics	Oct 28, 2020	- -

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, 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 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 Proline with Leucine at codon 1787 of the RYR1 protein, p.(Pro1787Leu). The maximum allele frequency for this variant among the six major gnomAD populations is SAS: 0.0413, 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	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. -

not provided Benign:4 Other:1

not provided, no classification provided	literature only	Leiden Muscular Dystrophy (RYR1)	-	- -
Benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Apr 01, 2024	RYR1: BS1, BS2 -
Likely benign, no assertion criteria provided	clinical testing	Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)	-	- -
Benign, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Nov 22, 2023	- -
Likely benign, no assertion criteria provided	clinical testing	Clinical Genetics, Academic Medical Center	-	- -

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

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. -

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

Likely benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jun 14, 2016

- -

Malignant hypothermia Benign:1

Benign, criteria provided, single submitter

clinical testing

Genomic Diagnostic Laboratory, Division of Genomic Diagnostics, Children's Hospital of Philadelphia

Mar 25, 2015

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.15
BayesDel_addAF	Benign	-0.52	T
BayesDel_noAF	Benign	-0.49
Cadd	Benign	18
Dann	Uncertain	0.99
Eigen	Benign	-0.92
Eigen_PC	Benign	-0.85
FATHMM_MKL	Benign	0.22	N
LIST_S2	Benign	0.84	T;T
MetaRNN	Benign	0.0031	T;T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	-0.14	N;N
MutationTaster	Benign	1.0	N;N;N
PrimateAI	Uncertain	0.61	T
PROVEAN	Uncertain	-2.9	D;D
REVEL	Benign	0.055
Sift	Benign	0.10	T;T
Polyphen		0.016	B;B
Vest4		0.32
MPC		0.66
ClinPred		0.020	T
GERP RS		-0.016
Varity_R		0.059
gMVP		0.53

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: rs34934920; hg19: chr19-38976655;