rs118192130

chr19-38570620-G-A

Variant summary

Our verdict is Pathogenic. Variant got 11 ACMG points: 11P and 0B. PM1 PM5 PP2 PP3_Moderate PP5_Strong

The NM_000540.3(RYR1):c.13673G>A(p.Arg4558Gln) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000359 in 1,613,898 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R4558W) has been classified as Likely pathogenic.

• Frequency:
  • Genomes: 𝑓 0.000013 (0 hom., cov: 32)
  • Exomes 𝑓: 0.000038 (0 hom.)
• Consequence: RYR1 NM_000540.3 missense
• Clinical Significance: Uncertain significance reviewed by expert panel P:8 U:6 O:1
• Conservation: PhyloP100: 9.92

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 Pathogenic. Variant got 11 ACMG points.

• PM1: In a hotspot region, there are 2 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 5 uncertain in NM_000540.3
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr19-38570619-C-T is described in ClinVar as [Uncertain_significance]. Clinvar id is 478187.Status of the report is reviewed_by_expert_panel, 3 stars. We mark this variant Likely_pathogenic, oryginal submissions are: {Likely_pathogenic=4, Uncertain_significance=2, Pathogenic=1}.
• PP2: Missense variant where missense usually causes diseases, RYR1
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.924
• PP5: Variant 19-38570620-G-A is Pathogenic according to our data. Variant chr19-38570620-G-A is described in ClinVar as [Uncertain_significance]. Clinvar id is 65984.Status of the report is reviewed_by_expert_panel, 3 stars. We mark this variant Likely_pathogenic, oryginal submissions are: {Uncertain_significance=5, Likely_pathogenic=6, not_provided=1, Pathogenic=1}. Variant chr19-38570620-G-A is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
RYR1	NM_000540.3	c.13673G>A	p.Arg4558Gln	missense_variant	94/106	ENST00000359596.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
RYR1	ENST00000359596.8	c.13673G>A	p.Arg4558Gln	missense_variant	94/106	5	NM_000540.3	A2

Frequencies

GnomAD3 genomes AF: 0.0000131 AC: 2 AN: 152100 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000294

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.0000358 AC: 9 AN: 251490 Hom.: 0 AF XY: 0.0000368 AC XY: 5 AN XY: 135918

Gnomad AFR exome AF: 0.0000615

Gnomad AMR exome AF: 0.0000289

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.000109

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000439

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000383 AC: 56 AN: 1461680 Hom.: 0 Cov.: 30 AF XY: 0.0000399 AC XY: 29 AN XY: 727146

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.0000224

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.000101

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.0000187

Gnomad4 NFE exome AF: 0.0000432

Gnomad4 OTH exome AF: 0.0000166

GnomAD4 genome AF: 0.0000131 AC: 2 AN: 152218 Hom.: 0 Cov.: 32 AF XY: 0.0000269 AC XY: 2 AN XY: 74424

Gnomad4 AFR AF: 0.00

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000294

Gnomad4 OTH AF: 0.00

Alfa AF: 0.0000556 Hom.: 0

Bravo AF: 0.00000378

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.000116 AC: 1

ExAC AF: 0.0000165 AC: 2

EpiCase AF: 0.0000545

EpiControl AF: 0.0000593

ClinVar

Significance: Uncertain significance

Submissions summary: Pathogenic:8 Uncertain:6 Other:1

Revision: reviewed by expert panel

Submissions by phenotype

Central core myopathy Pathogenic:3 Uncertain:2

Uncertain significance, no assertion criteria provided	research	CSER _CC_NCGL, University of Washington	Jun 01, 2014	- -
Likely pathogenic, criteria provided, single submitter	curation	Broad Center for Mendelian Genomics, Broad Institute of MIT and Harvard	Nov 16, 2020	The heterozygous p.Arg4558Gln variant in RYR1 was identified by our study in the compound heterozygous state, along with a variant of uncertain significance, in 1 individual with central core myopathy. The p.Arg4558Gln variant has been reported in at least 5 individuals of Belgian or unknown ethnicity with central core myopathy (PMID: 18253926, 25747005, 17226826) and segregated with disease in 2 affected relatives from 2 families. This variant has been identified in 0.01% (2/19952) of East Asian chromosomes by the Genome Aggregation Database (gnomAD, http://gnomad.broadinstitute.org; dbSNP ID: rs118192130). The p.Arg4558Gln variant has also been reported in ClinVar (Variation ID: 65984) with conflicting interpretations of pathogenicity. In vitro functional studies provide some evidence that the variant may impact protein function (PMID: 18253926). However, these types of assays may not accurately represent biological function. Computational prediction tools and conservation analyses suggest that this variant may impact the protein, though this information is not predictive enough to determine pathogenicity. The presence of this variant in combination with a reported likely pathogenic variant and in combination with a reported variant of uncertain significance that is confirmed in trans, and in 5 individuals with central core myopathy increases the likelihood that the variant is pathogenic (Variation ID: 65925, 133116; PMID: 18253926, 25747005, 17226826). Multiple variants in the same region as p.Arg4558Gln have been reported in association with disease in ClinVar, and the variant is located in a region of RYR1 that is essential to protein folding and stability, suggesting that this variant is in a hotspot and supports pathogenicity (PMID: 23069638). In summary, although additional studies are required to fully establish its clinical significance, this variant is likely pathogenic. ACMG/AMP Criteria applied: PM2_supporting, PS3_moderate, PP3, PM3_supporting, PM1, PP1 (Richards 2015). -
Pathogenic, no assertion criteria provided	curation	GeneReviews	May 11, 2010	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Baylor Genetics	Mar 02, 2018	This variant was determined to be of uncertain significance according to ACMG Guidelines, 2015 [PMID:25741868]. -
Likely pathogenic, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Jan 10, 2019	The RYR1 c.13673G>A (p.Arg4558Gln) variant has been reported in three studies in which it was found in a compound heterozygous state in a total of five probands with central core disease from three families (Kossugue et al. 2007; Monnier et al. 2008; Remiche et al. 2015). In two of the families, the heterozygous parent of the probands was shown to be unaffected, and in one family, the heterozygous sibling was also unaffected (Kossugue et al. 2007; Remiche et al. 2015). The p.Arg4558Gln variant was absent from 200 control chromosomes and is reported at a frequency of 0.00012 in the European American population of the Exome Sequencing Project. However, this frequency is based on one allele only, suggesting the variant is rare. Western blotting revealed reduced RYR1 protein expression in the muscle tissue of one proband (Monnier et al. 2008). The amino acid residue affected by the p.Arg4558Gln variant is evolutionarily conserved and is located in the M5 transmembrane fragment of the calcium channel. Based on the collective evidence, the p.Arg4558Gln variant is classified as likely pathogenic for pathogenicity for central core disease. This variant was observed by ICSL as part of a predisposition screen in an ostensibly healthy population. -

not provided Pathogenic:2 Uncertain:2 Other:1

not provided, no classification provided	literature only	Leiden Muscular Dystrophy (RYR1)	-	- -
Likely pathogenic, criteria provided, single submitter	clinical testing	Genetic Services Laboratory, University of Chicago	Mar 31, 2014	- -
Likely pathogenic, criteria provided, single submitter	clinical testing	GeneDx	May 09, 2023	Not observed at significant frequency in large population cohorts (gnomAD); 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: 26332594, 25637381, 17226826, 18253926, 25747005, 33458582, 35627144) -
Uncertain significance, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Jan 06, 2017	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Revvity Omics, Revvity	Jul 25, 2022	- -

Malignant hyperthermia, susceptibility to, 1 Uncertain:2

Uncertain significance, reviewed by expert panel	curation	ClinGen Malignant Hyperthermia Susceptibility Variant Curation Expert Panel, ClinGen	Apr 06, 2023	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 Arginine with Glutamine at codon 4558 of the RYR1 protein, p.(Arg4558Gln). The maximum allele frequency for this variant among the six major gnomAD populations is EAS: 0.0001, a frequency consistent with pathogenicity for MHS. This variant has been reported in individuals with a personal or family history of congenital myopathy. No functional studies were identified for this variant. This variant does not reside in a hotspot for pathogenic variants that contribute to MHS. A REVEL score >0.85 (0.957) supports a pathogenic status for this variant, PP3_Moderate. This variant has been classified as a Variant of Unknown Significance. Criteria implemented: PP3_Moderate. -
Uncertain significance, criteria provided, single submitter	clinical testing	All of Us Research Program, National Institutes of Health	Feb 05, 2024	This missense variant replaces arginine with glutamine at codon 4558 of the RYR1 protein. Computational prediction suggests that this variant may have deleterious impact on protein structure and function (internally defined REVEL score threshold >= 0.7, PMID: 27666373). To our knowledge, functional studies have not been reported for this variant. This variant has not been reported in individuals affected with autosomal dominant malignant hyperthermia in the literature, although this variant is associated with other phenotypes (ClinVar Variation ID: 65984). This variant has been identified in 10/282878 chromosomes in the general population by the Genome Aggregation Database (gnomAD). Due to insufficient evidence, this variant is classified as a Variant of Uncertain Significance for autosomal dominant malignant hyperthermia. -

RYR1-related condition Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Jun 02, 2023

The RYR1 c.13673G>A variant is predicted to result in the amino acid substitution p.Arg4558Gln. This variant has been reported in the compound heterozygous state in two siblings with central core disease with the heterozygous carrier parent showing no symptoms of RYR1-related disorders (Kossugue et al 2007. PubMed ID: 17226826). This variant was observed with a second RYR1 loss-of-function variant in four additional patients with congenital myopathy (Monnier N et al 2008. PubMed ID: 18253926; Remiche et al. 2015. PubMed ID: 25747005; Pinto et al. 2022. PubMed ID: 35548885). One of these patients was reported to have had surgery in the past with no adverse effects from anesthesia and carrier family members did not have symptoms (Remiche et al. 2015. PubMed ID: 25747005 ). A different substitution of this amino acid (p.Arg4558Trp) has also been reported in cases of autosomal recessive RYR1-related disorders (Gonzalez-Quereda L et al 2020. PubMed ID: 32403337; Abath Neto et al 2017. PubMed ID: 28818389). Of note, this variant has been reported in ClinVar by an ClinGen Expert Malignant Hyperthermia panel as uncertain in regard to MH susceptibility (https://www.ncbi.nlm.nih.gov/clinvar/variation/65984/). This variant is reported in 0.010% of alleles in individuals of East Asian descent in gnomAD (http://gnomad.broadinstitute.org/variant/19-39061260-G-A). In summary, we categorize the c.13673G>A variant as likely pathogenic for autosomal recessive RYR1-related disorders; however, the clinical significance of this variant is uncertain in regard to autosomal dominant RYR1-related disorders. -

Centronuclear myopathy Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Aug 11, 2020

The p.Arg4558Gln variant in RYR1 has been reported, in the compound heterozygous state, in 3 individuals with autosomal recessive central core myopathy and segregated with disease in 2 affected family members from 2 families (Kossugue 2007 PMID: 17226826, Monnier 2008 PMID: 18253926, Remiche 2015 PMID: 25747005).This variant has been reported in ClinVar (Variation ID 65984) and has also been identified in 2/19952 of East Asian chromosomes by gnomAD (http://gnomad.broadinstitute.org). Computational prediction tools and conservation analyses suggest that this variant may impact the protein, though this information is not predictive enough to determine pathogenicity. In summary, although additional studies are required to fully establish its clinical significance, this variant meets criteria to be classified as likely pathogenic for autosomal recessive central core myopathy. ACMG/AMP Criteria applied: PM3_Strong, PP3, PM2, PP1_Moderate. -

RYR1-Related Disorders Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Invitae

Jan 26, 2024

This sequence change replaces arginine, which is basic and polar, with glutamine, which is neutral and polar, at codon 4558 of the RYR1 protein (p.Arg4558Gln). The frequency data for this variant in the population databases is considered unreliable, as metrics indicate poor data quality at this position in the gnomAD database. This missense change has been observed in individuals with autosomal recessive central core disease (PMID: 17226826, 18253926, 25747005). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 65984). 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%. For these reasons, this variant has been classified as Pathogenic. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.90
BayesDel_addAF	Pathogenic	0.38	D
BayesDel_noAF	Pathogenic	0.49
Cadd	Pathogenic	26
Dann	Uncertain	0.99
Eigen	Pathogenic	0.94
Eigen_PC	Pathogenic	0.89
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Pathogenic	1.0	D;D
M_CAP	Pathogenic	0.75	D
MetaRNN	Pathogenic	0.92	D;D
MetaSVM	Pathogenic	1.1	D
MutationTaster	Benign	1.0	D;D;D
PrimateAI	Uncertain	0.78	T
PROVEAN	Uncertain	-3.5	D;D
REVEL	Pathogenic	0.96
Sift	Uncertain	0.0010	D;D
Polyphen		1.0	D;D
Vest4		0.84
MVP		1.0
MPC		0.66
ClinPred		0.90	D
GERP RS		5.1
Varity_R		0.63
gMVP		0.98

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: rs118192130; hg19: chr19-39061260;