rs137933390

chr19-38475335-A-G

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.4178A>G(p.Lys1393Arg) variant causes a missense change. The variant allele was found at a frequency of 0.00346 in 1,599,366 control chromosomes in the GnomAD database, including 20 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★★).

• Frequency:
  • Genomes: 𝑓 0.0028 (1 hom., cov: 32)
  • Exomes 𝑓: 0.0035 (19 hom.)
• Consequence: RYR1 NM_000540.3 missense
• Clinical Significance: Benign reviewed by expert panel U:5 B:18
• Conservation: PhyloP100: 4.86

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=0.011279523).
• BP6: Variant 19-38475335-A-G is Benign according to our data. Variant chr19-38475335-A-G is described in ClinVar as [Benign]. Clinvar id is 93269.Status of the report is reviewed_by_expert_panel, 3 stars. Variant chr19-38475335-A-G is described in Lovd as [Likely_benign]. Variant chr19-38475335-A-G is described in Lovd as [Benign].
• BS1: Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.00277 (421/152250) while in subpopulation NFE AF= 0.00476 (324/68008). AF 95% confidence interval is 0.00434. There are 1 homozygotes in gnomad4. There are 165 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
• BS2: High Homozygotes in GnomAdExome at 3 AD,AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
RYR1	NM_000540.3	c.4178A>G	p.Lys1393Arg	missense_variant	29/106	ENST00000359596.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
RYR1	ENST00000359596.8	c.4178A>G	p.Lys1393Arg	missense_variant	29/106	5	NM_000540.3	A2
RYR1	ENST00000355481.8	c.4178A>G	p.Lys1393Arg	missense_variant	29/105	1		P4
RYR1	ENST00000599547.6	c.4178A>G	p.Lys1393Arg	missense_variant, NMD_transcript_variant	29/80	2

Frequencies

GnomAD3 genomes AF: 0.00277 AC: 422 AN: 152132 Hom.: 1 Cov.: 32

Gnomad AFR AF: 0.00109

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00170

Gnomad ASJ AF: 0.000288

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00188

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00478

Gnomad OTH AF: 0.00239

GnomAD3 exomes AF: 0.00273 AC: 617 AN: 225862 Hom.: 3 AF XY: 0.00269 AC XY: 327 AN XY: 121580

Gnomad AFR exome AF: 0.00128

Gnomad AMR exome AF: 0.00227

Gnomad ASJ exome AF: 0.000105

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00225

Gnomad NFE exome AF: 0.00469

Gnomad OTH exome AF: 0.00194

GnomAD4 exome AF: 0.00353 AC: 5110 AN: 1447116 Hom.: 19 Cov.: 32 AF XY: 0.00344 AC XY: 2472 AN XY: 718420

Gnomad4 AFR exome AF: 0.000904

Gnomad4 AMR exome AF: 0.00209

Gnomad4 ASJ exome AF: 0.000116

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00210

Gnomad4 NFE exome AF: 0.00428

Gnomad4 OTH exome AF: 0.00245

GnomAD4 genome AF: 0.00277 AC: 421 AN: 152250 Hom.: 1 Cov.: 32 AF XY: 0.00222 AC XY: 165 AN XY: 74444

Gnomad4 AFR AF: 0.00108

Gnomad4 AMR AF: 0.00170

Gnomad4 ASJ AF: 0.000288

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00188

Gnomad4 NFE AF: 0.00476

Gnomad4 OTH AF: 0.00237

Alfa AF: 0.00406 Hom.: 6

Bravo AF: 0.00304

TwinsUK AF: 0.00431 AC: 16

ALSPAC AF: 0.00493 AC: 19

ESP6500AA AF: 0.00136 AC: 6

ESP6500EA AF: 0.00582 AC: 50

ExAC AF: 0.00245 AC: 297

Asia WGS AF: 0.000577 AC: 2 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Uncertain:5 Benign:18

Revision: reviewed by expert panel

Submissions by phenotype

not provided Uncertain:4 Benign:5

Likely benign, criteria provided, single submitter	clinical testing	GeneDx	Oct 06, 2020	Reported previously in individuals with features of RYR1-related disorders, but familial segregation information was not always included and some individuals were noted to have other potentially causative variants (Vukcevic et al., 2010; Dlamini et al., 2013; Loseth et al., 2013; Gillies et al., 2015); In silico analysis, which includes protein predictors and evolutionary conservation, supports that this variant does not alter protein structure/function; This variant is associated with the following publications: (PMID: 26332594, 20142353, 27153395, 25637381, 25985138, 23329375, 24195946, 25735680, 23628358, 28496993, 30788618, 30916033) -
Uncertain significance, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Jun 03, 2015	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Mayo Clinic Laboratories, Mayo Clinic	Dec 01, 2021	- -
Uncertain significance, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Apr 01, 2022	The RYR1 c.4178A>G, p.Lys1393Arg variant (rs137933390) has been identified in several individuals with clinical suspicion for malignant hyperthermia susceptibility (MHS) syndrome or other related myopathy (Bick 2017, Gillies 2015, Loseth 2013, Vukcevic 2010). Additionally, a cell line isolated from an MHS patient showed increased sensitivity to 4-chloro-m-cresol (Vukcevic 2010). However, variant has been identified at high allele frequency in several control populations, and is found in the non-Finnish European population with an allele frequency of 0.46% (537/ 115776 alleles, including 2 homozygotes) in the Genome Aggregation Database. Due to this high population frequency, the ClinGen Malignant Hyperthermia Susceptibility Variant Curation Expert Panel considers this variant benign with respect to autosomal dominant MHS (ClinVar Variation ID: 93269). However, this population frequency alone is not high enough alone to rule out a potential role with respect to the recessive myopathies associated with loss of function variation in RYR1. Therefore, while considered benign for MHS specifically, the overall classification of this variant is uncertain. References: Bick D et al. Successful Application of Whole Genome Sequencing in a Medical Genetics Clinic. J Pediatr Genet. 2017 Jun;6(2):61-76. PMID: 28496993 Gillies RL et al. Analysis of the entire ryanodine receptor type 1 and alpha 1 subunit of the dihydropyridine receptor (CACNA1S) coding regions for variants associated with malignant hyperthermia in Australian families. Anaesth Intensive Care. 2015 Mar;43(2):157-66. PMID: 25735680. Loseth S et al. A novel late-onset axial myopathy associated with mutations in the skeletal muscle ryanodine receptor (RYR1) gene. J Neurol. 2013 Jun;260(6):1504-10. PMID: 23329375. Vukcevic M et al. Functional properties of RYR1 mutations identified in Swedish patients with malignant hyperthermia and central core disease. Anesth Analg. 2010 Jul;111(1):185-90. PMID: 20142353. -
Uncertain significance, criteria provided, single submitter	clinical testing	Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics	Feb 22, 2017	- -
Likely benign, no assertion criteria provided	clinical testing	Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	-	- -
Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Jan 01, 2024	RYR1: BS2 -
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	Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	-	- -

Malignant hyperthermia, susceptibility to, 1 Benign:5

Likely benign, criteria provided, single submitter	clinical testing	Molecular Genetics, Royal Melbourne Hospital	Mar 30, 2023	This sequence change is predicted to replace lysine with arginine at codon 1393 of the RYR1 protein (p.(Lys1393Arg)). The lysine residue is conserved (100 vertebrates, UCSC), and there is a small physicochemical difference between lysine and arginine. It is not in an annotated domain. The variant is present in a large population cohort at a frequency of 0.46% in the European non-Finnish population (rs137933390, gnomAD v2.1.1 and v3.0). In comparison, the variant was present at a frequency of 0.46% in a cohort of individuals with malignant hyperthermia susceptibility (PMID: 24195946). This variant has been seen in at least 13 individuals with malignant hyperthermia susceptibility, including some individuals where another RYR1 variant was identified (PMID: 24195946, 19346234, 25960145, 23558838, 24433488, 25735680, 28326467), as well as being present in individuals with myopathy, rhabdomyolysis and exertional heat stroke (PMID: 22473935, 23628358, 23329375, 26565425, 28496993), although several authors acknowledge the high population frequency and comment that the variant is unlikely to be pathogenic. This variant has been shown not to segregate with the malignant hyperthermia susceptibility phenotype in two unrelated families, although the pedigrees have not been confirmed (PMID: 25658027). It has been reported in at least three further individuals without malignant hyperthermia (PMID: 25614869). Functional data from a lymphoblastoid cell line demonstrated 4-chloro-m-cresol induced calcium release at a lower concentration, however it is unclear whether this is a true reflection of the skeletal myocyte (PMID: 20142353). Multiple lines of computational evidence have conflicting predictions for the missense substitution (4/6 algorithms predict benign/neutral effect, 1/6 algorithms predict deleterious effect, 1/6 algorithms have an unknown prediction). Based on the classification guidelines RMH Modified ACMG Guidelines v1.3.0, this variant is classified as LIKELY BENIGN. The following criteria are met: BS1, BP5. -
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	Jul 12, 2022	- -
Benign, criteria provided, single submitter	research	Biesecker Lab/Clinical Genomics Section, National Institutes of Health	Jul 01, 2013	- -
Likely benign, no assertion criteria provided	research	CSER _CC_NCGL, University of Washington	Jun 01, 2014	- -

not specified Uncertain:1 Benign:1

Uncertain significance, criteria provided, single submitter	clinical testing	Athena Diagnostics	Apr 21, 2017	- -
Benign, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, University Medical Center Utrecht	-	- -

RYR1-related disorder Benign:2

Likely benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	Apr 01, 2022	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). -
Likely benign, criteria provided, single submitter	clinical testing	Invitae	Feb 01, 2024	- -

Malignant hyperthermia of anesthesia Benign:2

Likely benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Jun 14, 2016	- -
Benign, reviewed by expert panel	curation	ClinGen Malignant Hyperthermia Susceptibility Variant Curation Expert Panel, ClinGen	Jan 03, 2022	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 lysine with arginine at codon 1393 of the RYR1 protein, p.(Lys1393Arg). The maximum allele frequency for this variant among the six major gnomAD populations is NFE: 0.0046, 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. -

Congenital multicore myopathy with external ophthalmoplegia Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Feb 09, 2018

This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). No publications were found based on this search. Allele frequency data from public databases allowed determination this variant is unlikely to cause disease. Therefore, this variant is classified as likely benign. -

Central core myopathy Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Feb 09, 2018

This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). No publications were found based on this search. Allele frequency data from public databases allowed determination this variant is unlikely to cause disease. Therefore, this variant is classified as likely benign. -

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

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.077
BayesDel_addAF	Benign	-0.072	T
BayesDel_noAF	Uncertain	0.13
Cadd	Benign	22
Dann	Uncertain	1.0
Eigen	Benign	-0.056
Eigen_PC	Benign	0.090
FATHMM_MKL	Uncertain	0.94	D
LIST_S2	Benign	0.83	T;T
M_CAP	Benign	0.084	D
MetaRNN	Benign	0.011	T;T
MetaSVM	Uncertain	0.44	D
MutationAssessor	Benign	1.2	L;L
MutationTaster	Benign	0.57	D;D;D
PrimateAI	Uncertain	0.69	T
PROVEAN	Benign	-0.30	N;N
REVEL	Uncertain	0.56
Sift	Benign	0.34	T;T
Polyphen		0.39	B;B
Vest4		0.56
MVP		0.98
MPC		0.37
ClinPred		0.017	T
GERP RS		4.6
Varity_R		0.072
gMVP		0.54

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.060		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: rs137933390; hg19: chr19-38965975; COSMIC: COSV62094518;