rs193922868

chr19-38577955-G-A

Variant summary

Our verdict is Pathogenic. Variant got 13 ACMG points: 13P and 0B. PM1 PM5 PP2 PP5_Very_Strong

The NM_000540.3(RYR1):c.14210G>A(p.Arg4737Gln) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000013 in 1,461,886 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Pathogenic (★★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R4737W) has been classified as Likely pathogenic.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.000013 (0 hom.)
• Consequence: RYR1 NM_000540.3 missense
• Clinical Significance: Pathogenic reviewed by expert panel P:9 O:1
• Conservation: PhyloP100: 7.54

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 13 ACMG points.

• PM1: In a topological_domain Cytoplasmic (size 117) in uniprot entity RYR1_HUMAN there are 24 pathogenic changes around while only 4 benign (86%) in NM_000540.3
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr19-38577954-C-T is described in ClinVar as [Likely_pathogenic]. Clinvar id is 133060.Status of the report is reviewed_by_expert_panel, 3 stars.
• PP2: Missense variant where missense usually causes diseases, RYR1
• PP5: Variant 19-38577955-G-A is Pathogenic according to our data. Variant chr19-38577955-G-A is described in ClinVar as [Pathogenic]. Clinvar id is 133061.Status of the report is reviewed_by_expert_panel, 3 stars. Variant chr19-38577955-G-A is described in Lovd as [Likely_pathogenic]. Variant chr19-38577955-G-A is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
RYR1	NM_000540.3	c.14210G>A	p.Arg4737Gln	missense_variant	98/106	ENST00000359596.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
RYR1	ENST00000359596.8	c.14210G>A	p.Arg4737Gln	missense_variant	98/106	5	NM_000540.3	A2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD3 exomes AF: 0.00000398 AC: 1 AN: 251402 Hom.: 0 AF XY: 0.00000736 AC XY: 1 AN XY: 135904

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00000879

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000130 AC: 19 AN: 1461886 Hom.: 0 Cov.: 32 AF XY: 0.00000688 AC XY: 5 AN XY: 727244

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000162

Gnomad4 OTH exome AF: 0.0000166

GnomAD4 genome Cov.: 32

Bravo AF: 0.00000378

ExAC AF: 0.00000824 AC: 1

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:9 Other:1

Revision: reviewed by expert panel

Submissions by phenotype

not provided Pathogenic:4 Other:1

not provided, no classification provided	literature only	Leiden Muscular Dystrophy (RYR1)	-	- -
Pathogenic, criteria provided, single submitter	clinical testing	Revvity Omics, Revvity	Mar 25, 2019	- -
Pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Dec 02, 2022	Previously reported, using alternate nomenclature R4893Q, in association with malignant hyperthermia in multiple unrelated individuals (Monnier et al., 2005; Robinson et al., 2006; Gillies et al., 2008; Carpenter et al., 2009); Published functional studies demonstrate a damaging effect (Gomez et al., 2016); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Not observed at significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 16917943, 27558158, 25960145, 27663056, 28326467, 16163667, 30788618, 19648156, 30236257, 18564801) -
Pathogenic, criteria provided, single submitter	clinical testing	Greenwood Genetic Center Diagnostic Laboratories, Greenwood Genetic Center	Nov 16, 2020	PS3, PP3, PM1, PM2, PM5 -
Pathogenic, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	Feb 19, 2019	- -

Malignant hyperthermia, susceptibility to, 1 Pathogenic:3

Pathogenic, criteria provided, single submitter	clinical testing	Color Diagnostics, LLC DBA Color Health	Sep 05, 2023	This variant replaces arginine with glutamine at codon 4737 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). This variant is located in a region of the RYR1 protein considered to be a hotspot for pathogenic variants that contribute to malignant hyperthermia susceptibility (PMID: 21118704). A functional study has shown the mutant protein to exhibit hypersensitivity to an RYR1 agonist in calcium release assays (PMID: 36208971). This variant has been reported in over ten unrelated individuals affected with malignant hyperthermia susceptibility (PMID: 16163667, 18564801, 24433488, 30236257, 36208971). This variant has been shown to segregate with malignant hyperthermia susceptibility in 6 meioses in one family (PMID:18564801) and reported to segregate with disease in additional families (PMID: 30236257). Two related individuals who carry this variant have been reported to test negative in in vitro contracture tests (PMID: 30236257). This variant has been identified in 1/251402 chromosomes in the general population by the Genome Aggregation Database (gnomAD). A different missense variant occurring at the same codon, p.Arg4737Trp, is known to be associated with malignant hyperthermia susceptibility (ClinVar variation ID: 133060), indicating that arginine at this position is important for RYR1 protein function. Based on the available evidence, this variant is classified as Pathogenic. -
Pathogenic, criteria provided, single submitter	clinical testing	All of Us Research Program, National Institutes of Health	Jul 11, 2023	The c.14210G>A (p.Arg4737Gln) variant of the RYR1 gene replaces arginine with glutamine at codon 4737 of the RYR1 protein (p.Arg4737Gln). This missense change has been observed in more than 10 individuals with personal or family history of a malignant hyperthermia reaction, positive in vitro contracture test (IVCT) or caffeine halothane contracture test (CHCT) (PMID: 16163667, 18564801, 19648156, 25960145). This variant segregates with malignant hyperthermia syndrome (MHS) in more than 6 meioses (PMID:30236257, 18564801). However, in a different family two genotype positive/phenotype negative (IVCT-) individuals were identified. This variant is located at a mutational hot spot region that contributes to MHS (PMID: 21118704). Experimental studies have shown that this missense change affects RYR1 function (PMID: 27558158). Computational prediction (REVEL=0.89 PMID: 27666373) suggests that this variant may have deleterious impact on protein structure and function. Alteration affecting the same amino acid, c.14209C>T (p.Arg4737Trp), was classified as likely pathogenic by the expert panel (ClinVar ID:133060). Therefore, this c.14210G>A (p.Arg4737Gln) variant of RYR1 gene is classified as pathogenic. -
Pathogenic, reviewed by expert panel	curation	ClinGen Malignant Hyperthermia Susceptibility Variant Curation Expert Panel, ClinGen	May 20, 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 4737 of the RYR1 protein, p.(Arg4737Gln). The maximum allele frequency for this variant among the six major gnomAD populations is NFE: 0.000009, a frequency consistent with pathogenicity for MHS. This variant has been reported in 14 unrelated individuals who have a personal or family history of a malignant hyperthermia reaction, all of these individuals had a positive in vitro contracture test (IVCT) or caffeine halothane contracture test (CHCT) result (if the proband was unavailable for testing, a positive diagnostic test result in a mutation-positive relative was counted), PS4 (PMID:30236257, PMID:16163667, PMID:18564801, PMID:24433488, NZ MH investigation unit, MH Investigation Unit (MHIU), UHN, Toronto). This variant segregates with MHS in >6 meioses, PP1_Strong, (PMID:30236257 , PMID:18564801, MH Investigation Unit (MHIU), UHN, Toronto). However, in a different family two genotype positive/phenotype negative (IVCT-) individuals were identified, BS2_Moderate. Functional studies in HEK293 cells show an increased sensitivity to RYR1 agonists, PS3_Moderate, (PMID:36208971). This variant resides in a region of RYR1 considered to be a hotspot for pathogenic variants that contribute to MHS, PM1_Supporting (PMID: 21118704). A REVEL score >0.85 (0.89) supports a pathogenic status for this variant, PP3_Moderate. Based on using Bayes to combine criteria this variant is assessed as Pathogenic, (PMID: 29300386). Criteria implemented: PS3_Moderate, PS4, PM1_Supporting, PP1_Strong, PP3_Moderate, BS2_Moderate. -

RYR1-related disorder Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Invitae

May 22, 2023

This sequence change replaces arginine, which is basic and polar, with glutamine, which is neutral and polar, at codon 4737 of the RYR1 protein (p.Arg4737Gln). This variant is present in population databases (rs193922868, gnomAD 0.0009%). This missense change has been observed in individuals with malignant hyperthermia (PMID: 16163667, 18564801, 19648156, 25960145). ClinVar contains an entry for this variant (Variation ID: 133061). 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. Experimental studies have shown that this missense change affects RYR1 function (PMID: 27558158). For these reasons, this variant has been classified as Pathogenic. -

Congenital myopathy with fiber type disproportion;C0751951:Central core myopathy;C1840365:King Denborough syndrome;C1850674:Congenital multicore myopathy with external ophthalmoplegia;C2930980:Malignant hyperthermia, susceptibility to, 1 Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

Fulgent Genetics, Fulgent Genetics

Jul 14, 2021

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.41
BayesDel_addAF	Pathogenic	0.40	D
BayesDel_noAF	Pathogenic	0.33
Cadd	Uncertain	24
Dann	Uncertain	0.99
Eigen	Pathogenic	0.72
Eigen_PC	Pathogenic	0.69
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Uncertain	0.95	D;D
M_CAP	Uncertain	0.21	D
MetaRNN	Uncertain	0.73	D;D
MetaSVM	Pathogenic	1.0	D
MutationTaster	Benign	1.0	D;D;D
PrimateAI	Uncertain	0.67	T
PROVEAN	Uncertain	-3.0	D;D
REVEL	Pathogenic	0.89
Sift	Benign	0.10	T;T
Polyphen		1.0	D;D
Vest4		0.36
MutPred		0.82		.;Gain of phosphorylation at Y4733 (P = 0.2103);
MVP		1.0
MPC		0.66
ClinPred		0.98	D
GERP RS		4.9
Varity_R		0.33
gMVP		0.79

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: rs193922868; hg19: chr19-39068595;