rs121918592

chr19-38448712-G-Achr19-38448712-G-C

Variant summary

Our verdict is Pathogenic. Variant got 25 ACMG points: 25P and 0B. PS1_Very_Strong PM1 PM2 PP2 PP3_Strong PP5_Very_Strong

The NM_000540.3(RYR1):c.1021G>A(p.Gly341Arg) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000274 in 1,461,880 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 Pathogenic (★★★). Another nucleotide change resulting in same amino acid change has been previously reported as Pathogenicin ClinVar.

• Frequency:
  • Genomes: not found (cov: 31)
  • Exomes 𝑓: 0.0000027 (0 hom.)
• Consequence: RYR1 NM_000540.3 missense
• Clinical Significance: Pathogenic reviewed by expert panel P:9 O:2
• Conservation: PhyloP100: 8.04

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 25 ACMG points.

• PS1: Transcript NM_000540.3 (RYR1) is affected with MISSENSE_VARIANT having same AA change as one Pathogenic present in ClinVar as 132992
• PM1: In a domain MIR 5 (size 57) in uniprot entity RYR1_HUMAN there are 7 pathogenic changes around while only 1 benign (88%) in NM_000540.3
• PM2: Very rare variant in population databases, with high coverage
• PP2: Missense variant where missense usually causes diseases, RYR1
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.97
• PP5: Variant 19-38448712-G-A is Pathogenic according to our data. Variant chr19-38448712-G-A is described in ClinVar as [Pathogenic]. Clinvar id is 12969.Status of the report is reviewed_by_expert_panel, 3 stars. Variant chr19-38448712-G-A is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
RYR1	NM_000540.3	c.1021G>A	p.Gly341Arg	missense_variant	11/106	ENST00000359596.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
RYR1	ENST00000359596.8	c.1021G>A	p.Gly341Arg	missense_variant	11/106	5	NM_000540.3	A2
RYR1	ENST00000355481.8	c.1021G>A	p.Gly341Arg	missense_variant	11/105	1		P4
RYR1	ENST00000599547.6	c.1021G>A	p.Gly341Arg	missense_variant, NMD_transcript_variant	11/80	2

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome AF: 0.00000274 AC: 4 AN: 1461880 Hom.: 0 Cov.: 31 AF XY: 0.00000413 AC XY: 3 AN XY: 727236

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: 0.00000360

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 31

Bravo AF: 0.00000378

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:9 Other:2

Revision: reviewed by expert panel

Submissions by phenotype

Malignant hyperthermia, susceptibility to, 1 Pathogenic:4 Other:1

Pathogenic, reviewed by expert panel	curation	ClinGen Malignant Hyperthermia Susceptibility Variant Curation Expert Panel, ClinGen	Mar 18, 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 glycine with arginine at codon 341 of the RYR1 protein p.(Gly341Arg), c.1021G>A. This variant is not present in a large population database (gnomAD). This variant has been reported in 71 unrelated probands who have a personal or family history of a malignant hyperthermia reaction and a positive in vitro contracture test (IVCT) or caffeine halothane contracture test (CHCT) result (when the proband was unavailable for testing a positive diagnostic test result in a mutation positive relative was counted), PS4 ( PMID:30236257, PMID:16163667, PMID: 8012359 and others). Functional studies in HEK293 cells show an increased sensitivity to RYR1 agonists, PS3_Moderate (PMID:26115329). This variant resides in a region of RYR1 considered to be a hotspot for pathogenic variants that contribute to MHS, PM1 (PMID: 21118704). This variant segregates with MHS in 66 individuals, PP1_Strong ( PMID: 8012359, PMID:9106529, PMID:17710899 and others). A REVEL score > 0.85 supports pathogenicity,PP3_Moderate. Based on using Bayes to combine criteria this variant is assessed as Pathogenic, (PMID: 29300386). Criteria implemented: PS4, PS3_Moderate, PM1, PP1_Strong, PP3_Moderate, BS2_Moderate. -
risk factor, no assertion criteria provided	literature only	OMIM	Oct 01, 1998	- -
Pathogenic, criteria provided, single submitter	clinical testing	Molecular Genetics, Royal Melbourne Hospital	Nov 05, 2023	This sequence change in RYR1 is predicted to replace glycine with arginine at codon 341, p.(Gly341Arg). The glycine residue is highly conserved (100 vertebrates, UCSC), and is located in exon 11 in the N-terminal region, amino acids 1-552, which is defined as a mutational hotspot. There is a large physicochemical difference between glycine and arginine. This variant is absent from the population database gnomAD v2.1 and v3.1. This variant has been reported in multiple families with malignant hyperthermia susceptibility (MHS) confirmed by in vitro contracture testing (IVCT) and/or a personal/family history of an anaesthetic reaction, and it segregates with MHS in multiple families (PMID: 30236257). This variant has been observed in at least one family with a negative IVCT (PMID: 30236257). The variant demonstrates significantly enhanced sensitivity to calcium release in HEK293 cells indicating that this variant impacts protein function (PMID: 9334205, 26115329). Computational evidence predicts a deleterious effect for the missense substitution (REVEL = 0.864). Based on the classification scheme RMH Modified ACMG/AMP Guidelines v1.6.1, this variant is classified as PATHOGENIC. Following criteria are met: PS4, PP1_Strong, PM1, PP3_Moderate, PS3_Moderate, BS2_Moderate. -
Pathogenic, criteria provided, single submitter	clinical testing	Color Diagnostics, LLC DBA Color Health	Apr 18, 2023	This missense variant replaces glycine with arginine at codon 341 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). Functional studies using HEK293 cells and dyspedic myotubes have shown this variant increases sensitivity to RYR1 agonists compared to wild type RYR1 (PMID: 9334205, 9873004, 12732639, 26115329). This variant has been reported in over 50 families and/or individuals affected with malignant hyperthermia (PMID: 8825043, 9106529, 16163667, 18564801, 19648156, 24433488, 30236257). This variant has not been identified in the general population by the Genome Aggregation Database (gnomAD). 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	Aug 15, 2023	This missense variant replaces glycine with arginine at codon 341 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). Functional studies using HEK293 cells and dyspedic myotubes have shown this variant increases sensitivity to RYR1 agonists compared to wild type RYR1 (PMID: 9334205, 9873004, 12732639, 26115329). This variant has been reported in over 50 families and/or individuals affected with malignant hyperthermia (PMID: 8825043, 9106529, 16163667, 18564801, 19648156, 24433488, 30236257). This variant has not been identified in the general population by the Genome Aggregation Database (gnomAD). Based on the available evidence, this variant is classified as Pathogenic. -

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	May 06, 2019	- -
Likely pathogenic, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Sep 05, 2014	- -
Pathogenic, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	Mar 15, 2018	- -
Pathogenic, criteria provided, single submitter	clinical testing	Athena Diagnostics	Jun 23, 2022	This variant has been identified in multiple unrelated individuals with susceptibility to malignant hyperthermia (MHS) and associates with MHS in multiple families. This variant has not been reported in large, multi-ethnic general populations (http://gnomad.broadinstitute.org). In some published literature, this variant is referred to as G342R. Assessment of experimental evidence suggests this variant results in abnormal protein function. Variant increased sensitivity to RYR1 activators (PMID:26115329, 9334205, 12732639). -

RYR1-Related Disorders Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Invitae

Jan 13, 2024

This sequence change replaces glycine, which is neutral and non-polar, with arginine, which is basic and polar, at codon 341 of the RYR1 protein (p.Gly341Arg). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individuals with malignant hyperthermia (PMID: 8012359, 8825043, 19648156, 24433488). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 12969). 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) has been performed at Invitae for this missense variant, however the output from this modeling did not meet the statistical confidence thresholds required to predict the impact of this variant on RYR1 protein function. Experimental studies have shown that this missense change affects RYR1 function (PMID: 9334205, 9873004, 12732639). For these reasons, this variant has been classified as Pathogenic. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.96
BayesDel_addAF	Pathogenic	0.43	D
BayesDel_noAF	Pathogenic	0.38
Cadd	Pathogenic	26
Dann	Uncertain	1.0
Eigen	Uncertain	0.61
Eigen_PC	Uncertain	0.56
FATHMM_MKL	Uncertain	0.97	D
LIST_S2	Pathogenic	1.0	D;D
M_CAP	Pathogenic	0.51	D
MetaRNN	Pathogenic	0.97	D;D
MetaSVM	Uncertain	0.48	D
MutationAssessor	Uncertain	2.2	M;M
MutationTaster	Benign	1.0	D;D;D
PrimateAI	Uncertain	0.77	T
PROVEAN	Pathogenic	-6.6	D;D
REVEL	Pathogenic	0.86
Sift	Pathogenic	0.0	D;D
Polyphen		1.0	D;D
Vest4		0.77
MutPred		0.87		Loss of sheet (P = 0.0457);Loss of sheet (P = 0.0457);
MVP		0.97
MPC		1.1
ClinPred		1.0	D
GERP RS		3.6
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.87
gMVP		0.69

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.030		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: rs121918592; hg19: chr19-38939352;