rs147136339

chr19-38543551-A-G

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 2P and 1B. PP2 PP3 BP4

The NM_000540.3(RYR1):c.11798A>G(p.Tyr3933Cys) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00117 in 1,614,082 control chromosomes in the GnomAD database, including 3 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.0011 (0 hom., cov: 32)
  • Exomes 𝑓: 0.0012 (3 hom.)
• Consequence: RYR1 NM_000540.3 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:17 B:3 O:1
• Conservation: PhyloP100: 9.14

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 Uncertain_significance. Variant got 1 ACMG points.

• PP2: Missense variant where missense usually causes diseases, RYR1
• PP3: Multiple lines of computational evidence support a deleterious effect 10: AlphaMissense, BayesDel_addAF, BayesDel_noAF, Cadd, Eigen, M_CAP, phyloP100way_vertebrate, PrimateAI, PROVEAN, REVEL [when Dann, max_spliceai, FATHMM_MKL, MetaRNN, MutationTaster was below the threshold]
• BP4: Computational evidence support a benign effect (MetaRNN=0.3310064).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
RYR1	NM_000540.3	c.11798A>G	p.Tyr3933Cys	missense_variant	86/106	ENST00000359596.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
RYR1	ENST00000359596.8	c.11798A>G	p.Tyr3933Cys	missense_variant	86/106	5	NM_000540.3	A2

Frequencies

GnomAD3 genomes AF: 0.00109 AC: 166 AN: 152094 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.0000966

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00255

Gnomad ASJ AF: 0.00144

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000829

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00165

Gnomad OTH AF: 0.000958

GnomAD3 exomes AF: 0.000867 AC: 218 AN: 251418 Hom.: 0 AF XY: 0.000949 AC XY: 129 AN XY: 135908

Gnomad AFR exome AF: 0.0000615

Gnomad AMR exome AF: 0.000896

Gnomad ASJ exome AF: 0.000694

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.000621

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00136

Gnomad OTH exome AF: 0.000815

GnomAD4 exome AF: 0.00118 AC: 1723 AN: 1461870 Hom.: 3 Cov.: 37 AF XY: 0.00122 AC XY: 886 AN XY: 727240

Gnomad4 AFR exome AF: 0.000119

Gnomad4 AMR exome AF: 0.000984

Gnomad4 ASJ exome AF: 0.000574

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.000533

Gnomad4 FIN exome AF: 0.0000187

Gnomad4 NFE exome AF: 0.00140

Gnomad4 OTH exome AF: 0.000828

GnomAD4 genome AF: 0.00109 AC: 166 AN: 152212 Hom.: 0 Cov.: 32 AF XY: 0.00107 AC XY: 80 AN XY: 74432

Gnomad4 AFR AF: 0.0000963

Gnomad4 AMR AF: 0.00255

Gnomad4 ASJ AF: 0.00144

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000830

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.00165

Gnomad4 OTH AF: 0.000948

Alfa AF: 0.00137 Hom.: 1

Bravo AF: 0.00102

TwinsUK AF: 0.000809 AC: 3

ALSPAC AF: 0.000259 AC: 1

ESP6500AA AF: 0.000227 AC: 1

ESP6500EA AF: 0.00116 AC: 10

ExAC AF: 0.000923 AC: 112

Asia WGS AF: 0.000289 AC: 1 AN: 3478

EpiCase AF: 0.00191

EpiControl AF: 0.00172

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:17 Benign:3 Other:1

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not provided Uncertain:6 Benign:1 Other:1

Uncertain significance, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	Aug 15, 2016	- -
not provided, no classification provided	literature only	Leiden Muscular Dystrophy (RYR1)	-	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Mayo Clinic Laboratories, Mayo Clinic	Feb 12, 2020	- -
Uncertain significance, criteria provided, single submitter	clinical testing	GeneDx	May 17, 2023	Y3933C and R3366H reported in cis, and in conjunction with an additional RYR1 variant on the opposite allele, have been reported in patients with core myopathies as well as malignant hyperthermia susceptibility in some cases (Amburgey et al., 2013; Kraeva et al., 2015; Snoeck et al., 2015); Patients with only Y3933C and R3366H variants were reported to have malignant hyperthermia susceptibility or to be unaffected (Snoeck et al., 2015; Kraeva et al., 2015); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 36628841, 30788618, 30611313, 31321302, 32125936, 25637381, 20681998, 24055113, 25747005, 24950660, 23558838, 25960145, 23919265, 25735680, 22473935, 21674524, 25958340, 28269792, 28259615, 26332594, 25214167, 18564801, 30155738, 25658027, 30932294, 31517061, 32236737, 32403337, 35207755, 33646171, 34008892, 33726816, 32528171, 35428369) -
Uncertain significance, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Mar 01, 2018	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Genetic Services Laboratory, University of Chicago	Apr 29, 2014	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Revvity Omics, Revvity	Nov 16, 2022	- -
Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Apr 01, 2024	RYR1: PP3, BS1 -

Malignant hyperthermia, susceptibility to, 1 Uncertain:4 Benign:2

Likely benign, criteria provided, single submitter	clinical testing	Color Diagnostics, LLC DBA Color Health	Mar 20, 2023	- -
Uncertain significance, criteria provided, single submitter	clinical testing	MGZ Medical Genetics Center	Jul 27, 2022	- -
Uncertain significance, no assertion criteria provided	clinical testing	Zotz-Klimas Genetics Lab, MVZ Zotz Klimas	Oct 09, 2023	- -
Uncertain significance, criteria provided, single submitter	research	Biesecker Lab/Clinical Genomics Section, National Institutes of Health	Jul 01, 2013	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Mendelics	May 20, 2022	- -
Likely benign, no assertion criteria provided	research	CSER _CC_NCGL, University of Washington	Jun 01, 2014	- -

Central core myopathy Uncertain:2

Uncertain significance, criteria provided, single submitter	clinical testing	Baylor Genetics	May 05, 2019	This variant was determined to be of uncertain significance according to ACMG Guidelines, 2015 [PMID:25741868]. -
Uncertain significance, criteria provided, single submitter	clinical testing	Laboratory of Medical Genetics, National & Kapodistrian University of Athens	Oct 01, 2021	- -

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Oct 11, 2023

Variant summary: RYR1 c.11798A>G (p.Tyr3933Cys) results in a non-conservative amino acid change located in the RyR/IP3R Homology associated domain (IPRIPR013662) of the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 0.00087 in 251418 control chromosomes (gnomAD). c.11798A>G has been reported in the literature in cis with c.10097G>A and c.4711A>G in individuals affected with RYR1-Associated Myopathy (malignant hyperthermia (MH), congenital myopathy, central core disease (CCD), and multi minicore disease (MmD) (examples: Duarte_2011, Rocha_2014, Savarese_2014, Fiszer_2015, Snoeck_2015, Gillies_2015, Kraeva_2015, Garibaldi_2019, Granger_2023). It is unclear if one of the three variants or the combined effect of these mutations are causative for the RYR1-associated diseases in reported individuals. The following publications have been ascertained in the context of this evaluation (PMID: 30611313, 21674524, 25658027, 25960145, 24950660, 25214167, 25735680, 25958340, 36628841). Thirteen submitters have cited clinical-significance assessments for this variant to ClinVar after 2014 and classified the variant as VUS (n=11), likely benign (n=1), and likely pathogenic (n=1). Based on the evidence outlined above, the variant was classified as uncertain significance. -

RYR1-related disorder Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Invitae

Jan 31, 2024

This sequence change replaces tyrosine, which is neutral and polar, with cysteine, which is neutral and slightly polar, at codon 3933 of the RYR1 protein (p.Tyr3933Cys). This variant is present in population databases (rs147136339, gnomAD 0.1%), and has an allele count higher than expected for a pathogenic variant. Three missense variants, p.Ile1571Val, p.Arg3366His, and p.Tyr3933Cys, which includes this variant (p.Tyr3933Cys), have been reported together in multiple individuals and families affected with RYR1-related disorders including malignant hyperthermia (MH) syndrome, congenital myopathy, central core disease (CCD), and multi minicore disease (MmD). In some cases, the phase of the three variants along with additional RYR1 variants was established, while in other cases it could not be determined. It is therefore unclear if one of the three variants or the additive effect of some or all of these mutations are causative for the RYR1-associated diseases in reported individuals (PMID: 25958340, 25735680, 25214167, 24950660, 25960145, 25658027, 21674524, 18564801, 20681998, 23558838, 30611313). ClinVar contains an entry for this variant (Variation ID: 133021). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is expected to disrupt RYR1 protein function with a positive predictive value of 95%. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. -

See cases Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Laboratorio de Genetica e Diagnostico Molecular, Hospital Israelita Albert Einstein

Jul 11, 2020

ACMG classification criteria: PS4, PM3, PP3 -

RYR1-related myopathy Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Molecular Genetics, Royal Melbourne Hospital

Apr 11, 2023

This sequence change in RYR1 is predicted to replace tyrosine with cysteine at codon 3933, p.(Tyr3933Cys). The tyrosine residue is highly conserved (100 vertebrates, UCSC), and is located in exon 86. There is a large physicochemical difference between tyrosine and cysteine. The highest population minor allele frequency in the population database gnomAD v2.1 is 0.13% (172/129,120 alleles) in the European (non-Finnish) population. This variant is almost always reported in a haplotype with two other RYR1 missense variants, p.[(Ile1571Val);(Arg3366His);(Tyr3933Cys)]. The haplotype has been detected in at least 19 individuals with a phenotype consistent with RYR1-related myopathy with/without malignant hyperthermia susceptibility (MHS). Of those individuals, 14 were compound heterozygous for the variant and a pathogenic or likely pathogenic variant and 8 of those were confirmed in trans by parental/family testing (PMID: 22473935, 23394784, 24950660, 25958340, 25960145, 30611313, 32236737, 35428369). The haplotype segregates with myopathy in a recessive mode of inheritance in at least one family, and there is conflicting evidence for segregation with MHS (PMID: 22473935, 23394784, 25958340). There is limited evidence that the monoallelic haplotype is associated with RYR1-related disease, it has been detected in individuals that unaffected, with MHS, and symptomatic hyperCKaemia (PMID: 25958340, 28259615, 31517061, 32236737). To our knowledge, the variant has not been detected alone. Multiple lines of computational evidence predict a deleterious effect for the missense substitution (5/5 algorithms). Based on the classification scheme RMH Modified ACMG Guidelines v1.5.1, this variant is classified as a VARIANT OF UNCERTAIN SIGNIFICANCE. Following criteria are met: PP3. The haplotype is classified as LIKELY PATHOGENIC. Following criteria are met: PM3_VeryStrong, PP1. -

Congenital myopathy with fiber type disproportion;C0751951:Central core myopathy;C1850674:Congenital multicore myopathy with external ophthalmoplegia;C2930980:Malignant hyperthermia, susceptibility to, 1 Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Fulgent Genetics, Fulgent Genetics

Oct 31, 2018

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.98
BayesDel_addAF	Pathogenic	0.27	D
BayesDel_noAF	Pathogenic	0.57
Cadd	Pathogenic	26
Dann	Benign	0.97
Eigen	Pathogenic	0.72
Eigen_PC	Uncertain	0.64
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Pathogenic	1.0	D;D
M_CAP	Pathogenic	0.72	D
MetaRNN	Benign	0.33	T;T
MetaSVM	Pathogenic	0.90	D
MutationTaster	Benign	1.0	D;D;D
PrimateAI	Pathogenic	0.93	D
PROVEAN	Pathogenic	-7.2	D;D
REVEL	Pathogenic	0.98
Sift	Pathogenic	0.0	D;D
Polyphen		1.0	D;D
Vest4		0.84
MVP		1.0
MPC		0.75
ClinPred		0.32	T
GERP RS		4.1
Varity_R		0.81
gMVP		0.97

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: rs147136339; hg19: chr19-39034191; COSMIC: COSV62113208; COSMIC: COSV62113208;