chr19-38566986-G-C

Position:

chr19-38566986-G-C

Variant summary

Our verdict is Benign. Variant got -8 ACMG points: 0P and 8B. BA1

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 Aspartic Acid with Histidine at codon 4505 of the RYR1 protein, p.(Asp4505His). The maximum allele frequency for this variant among the six major gnomAD populations is NFE: 0.0054, 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. LINK:https://erepo.genome.network/evrepo/ui/classification/CA024057/MONDO:0007783/012

Frequency

Genomes: 𝑓 0.0033 ( 0 hom., cov: 31)

Exomes 𝑓: 0.0056 ( 23 hom. )

Consequence

RYR1
NM_000540.3 missense

Scores

Splicing: ADA: 0.002327

Clinical Significance

Benign reviewed by expert panel U:3B:19O:1

Conservation

PhyloP100: 2.97

Variant links:

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]

RYR1 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -8 ACMG points.

BA1

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 link	c.13513G>C	p.Asp4505His	missense_variant	92/106	ENST00000359596.8	NP_000531.2	P21817-1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
RYR1	ENST00000359596.8 link	c.13513G>C	p.Asp4505His	missense_variant	92/106	5	NM_000540.3	ENSP00000352608.2		P21817-1

Frequencies

GnomAD3 genomes

AF:

0.00332

AC:

505

AN:

152106

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00123

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00190

Gnomad ASJ

AF:

0.00490

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00207

Gnomad FIN

AF:

0.00123

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00562

Gnomad OTH

AF:

0.00144

GnomAD3 exomes

AF:

0.00337

AC:

696

AN:

206260

Hom.:

AF XY:

0.00361

AC XY:

400

AN XY:

110706

show subpopulations

Gnomad AFR exome

AF:

0.00117

Gnomad AMR exome

AF:

0.00130

Gnomad ASJ exome

AF:

0.00422

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00266

Gnomad FIN exome

AF:

0.00181

Gnomad NFE exome

AF:

0.00545

Gnomad OTH exome

AF:

0.00287

GnomAD4 exome

AF:

0.00556

AC:

8003

AN:

1438904

Hom.:

Cov.:

AF XY:

0.00547

AC XY:

3901

AN XY:

713364

show subpopulations

Gnomad4 AFR exome

AF:

0.000906

Gnomad4 AMR exome

AF:

0.00148

Gnomad4 ASJ exome

AF:

0.00471

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00267

Gnomad4 FIN exome

AF:

0.00164

Gnomad4 NFE exome

AF:

0.00655

Gnomad4 OTH exome

AF:

0.00452

GnomAD4 genome

AF:

0.00332

AC:

505

AN:

152224

Hom.:

Cov.:

AF XY:

0.00321

AC XY:

239

AN XY:

74424

show subpopulations

Gnomad4 AFR

AF:

0.00123

Gnomad4 AMR

AF:

0.00190

Gnomad4 ASJ

AF:

0.00490

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00207

Gnomad4 FIN

AF:

0.00123

Gnomad4 NFE

AF:

0.00562

Gnomad4 OTH

AF:

0.00143

Alfa

AF:

0.00353

Hom.:

Bravo

AF:

0.00331

TwinsUK

AF:

0.00566

AC:

ALSPAC

AF:

0.00701

AC:

ESP6500AA

AF:

0.00136

AC:

ESP6500EA

AF:

0.00431

AC:

ExAC

AF:

0.00330

AC:

398

Asia WGS

AF:

0.000866

AC:

AN:

3478

ClinVar

Significance: Benign

Submissions summary: Uncertain:3Benign:19Other:1

Revision: reviewed by expert panel

LINK: link

Submissions by phenotype

not provided

Uncertain:2Benign:6

Uncertain significance, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Jul 22, 2016	- -
Likely benign, no assertion criteria provided	clinical testing	Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	-	- -
Likely benign, no assertion criteria provided	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	-	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Athena Diagnostics	Aug 12, 2021	- -
Likely benign, criteria provided, single submitter	clinical testing	GeneDx	Sep 14, 2020	This variant is associated with the following publications: (PMID: 18813041, 23476141, 27147545, 23394784, 22473935, 24195946, 23329375, 25735680, 21918424, 27153395, 26332594, 27058611, 27663056, 28326467, 26019235, 30842289, 32381029) -
Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Nov 01, 2024	RYR1: BS2 -
Likely benign, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, University Medical Center Utrecht	-	- -
Likely benign, no assertion criteria provided	clinical testing	Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)	-	- -

Malignant hyperthermia, susceptibility to, 1

Benign:5

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 Aspartic Acid with Histidine at codon 4505 of the RYR1 protein, p.(Asp4505His). The maximum allele frequency for this variant among the six major gnomAD populations is NFE: 0.0054, 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	Color Diagnostics, LLC DBA Color Health	Sep 01, 2022	- -
Benign, criteria provided, single submitter	clinical testing	Mendelics	Aug 22, 2023	- -
Benign, criteria provided, single submitter	clinical testing	All of Us Research Program, National Institutes of Health	Sep 27, 2024	- -

Malignant hyperthermia of anesthesia

Benign:2Other:1

Likely benign, criteria provided, single submitter	research	CSER _CC_NCGL, University of Washington	Mar 11, 2015	- -
not provided, no classification provided	phenotyping only	GenomeConnect, ClinGen	-	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	Illumina Laboratory Services, Illumina	Jun 14, 2016	- -

not specified

Benign:2

Likely benign, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Jun 01, 2023	Variant summary: RYR1 c.13513G>C (p.Asp4505His) results in a non-conservative amino acid change located in the ryanodine receptor TM 4-6 domain (IPR009460) of the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. 4/4 computational tools predict no significant impact on normal splicing. However, these predictions have yet to be confirmed by functional studies. The variant allele was found at a frequency of 0.0034 in 206460 control chromosomes, including 2 homozygotes, and predominantly at a frequency of 0.0054 within the Non-Finnish European subpopulation in the gnomAD database. The observed variant frequency within Non-Finnish European control individuals in the gnomAD database is higher than the estimated maximal expected allele frequency for a pathogenic variant in RYR1 causing Malignant Hyperthermia Susceptibility phenotype determined by the ClinGen Malignant Hyperthermia Susceptibility Variant Curation Expert Panel (0.0054 vs 0.0038; Johnston_2021), suggesting that the variant is a benign polymorphism found primarily in populations of Non-Finnish European origin. c.13513G>C has been reported in the literature in individuals affected with malignant hyperthermia susceptibility, King-Denborough syndrome, congenital myopathy, RYR1-related late-onset axial myopathy, core myopathy, idiopathic hyperCKemia and atrioventricular septal defect; however no strong evidences of pathogenicity were found in these studies (e.g. Malandrini_2008, Groom_2011, Klein_2012, Maggi_2013, Loseth_2013, Klingler_2014, Gillies_2015, Priest_2016, Jokela_2019, Elliott_2022, Fusto_2022). Thus, these reports do not provide unequivocal conclusions about association of the variant with Malignant Hyperthermia Susceptibility or other RYR2-related disorders. This variant was found to cause a modest increase in caffeine sensitivity as compared to the wild type protein, and to further enhance such sensitivity when present in cis or trans with another variant, p.R3983C (Groom_2011). Twelve submitters, including the ClinGen Malignant Hyperthermia Susceptibility Variant Curation Expert Panel, have provided clinical-significance assessments for this variant to ClinVar after 2014 and classified the variant as benign (n=2)/likely benign (n=6) or VUS (n=4). Based on the evidence outlined above, the variant was classified as likely benign. -
Likely benign, criteria provided, single submitter	clinical testing	Genetic Services Laboratory, University of Chicago	Jul 07, 2020	- -

RYR1-related disorder

Benign:2

Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Feb 01, 2024	- -
Likely benign, no assertion criteria provided	clinical testing	PreventionGenetics, part of Exact Sciences	Jul 16, 2021	This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Congenital hip dislocation;C0699743:Congenital muscular dystrophy;C0746674:Generalized muscle weakness;C4021726:EMG: myopathic abnormalities

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Centre for Mendelian Genomics, University Medical Centre Ljubljana

Nov 14, 2014

- -

Myopathy, progressive axial with cataracts

Benign:1

Likely benign, no assertion criteria provided

research

CSER _CC_NCGL, University of Washington

Jun 01, 2014

- -

Congenital myopathy with fiber type disproportion;C1840365:King Denborough syndrome;C1850674:Congenital multicore myopathy with external ophthalmoplegia;C2930980:Malignant hyperthermia, susceptibility to, 1;C5830701:Central core myopathy

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Fulgent Genetics, Fulgent Genetics

Apr 06, 2022

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.72

BayesDel_addAF

Benign

-0.012

BayesDel_noAF

Pathogenic

0.21

CADD

Benign

DANN

Benign

0.46

DEOGEN2

Pathogenic

0.85

.;D

Eigen

Uncertain

0.48

Eigen_PC

Uncertain

0.35

FATHMM_MKL

Uncertain

0.80

LIST_S2

Uncertain

0.94

D;D

M_CAP

Pathogenic

0.35

MetaRNN

Benign

0.028

T;T

MetaSVM

Pathogenic

0.86

MutationAssessor

Uncertain

2.5

.;M

PrimateAI

Uncertain

0.66

PROVEAN

Uncertain

-4.0

D;D

REVEL

Pathogenic

0.66

Sift

Uncertain

0.0050

D;D

Polyphen

1.0

D;D

Vest4

0.77

MVP

0.99

MPC

0.68

ClinPred

0.053

GERP RS

3.9

Varity_R

0.57

gMVP

0.57

Splicing

Name

Calibrated prediction

Score

Prediction

dbscSNV1_ADA

Benign

0.0023

dbscSNV1_RF

Benign

0.020

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over