rs193922751

chr19-38444191-G-A

Variant summary

Our verdict is Likely pathogenic. Variant got 9 ACMG points: 9P and 0B. PM1 PM2 PP2 PP3_Strong

The NM_000540.3(RYR1):c.467G>A(p.Arg156Lys) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★★). Synonymous variant affecting the same amino acid position (i.e. R156R) has been classified as Likely benign.

• Frequency: Genomes: not found (cov: 32)
• Consequence: RYR1 NM_000540.3 missense
• Clinical Significance: Uncertain significance reviewed by expert panel U:3 O:1
• Conservation: PhyloP100: 9.96

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 Likely_pathogenic. Variant got 9 ACMG points.

• PM1: In a hotspot region, there are 3 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 2 benign, 7 uncertain 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, 0.973

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
RYR1	NM_000540.3	c.467G>A	p.Arg156Lys	missense_variant	6/106	ENST00000359596.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
RYR1	ENST00000359596.8	c.467G>A	p.Arg156Lys	missense_variant	6/106	5	NM_000540.3	A2
RYR1	ENST00000355481.8	c.467G>A	p.Arg156Lys	missense_variant	6/105	1		P4
RYR1	ENST00000599547.6	c.467G>A	p.Arg156Lys	missense_variant, NMD_transcript_variant	6/80	2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:3 Other:1

Revision: reviewed by expert panel

Submissions by phenotype

not provided Uncertain:1 Other:1

not provided, no classification provided	literature only	Leiden Muscular Dystrophy (RYR1)	-	- -
Uncertain significance, criteria provided, single submitter	clinical testing	GeneDx	Sep 14, 2020	Not observed in large population cohorts (Lek et al., 2016); 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: 19541610, 16917943, 16835904) -

Malignant hyperthermia, susceptibility to, 1 Uncertain:1

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 lysine at codon 156 of the RYR1 protein, p.(Arg156Lys). This variant was not present in a large population database (gnomAD) at the time this variant was interpreted. This variant has been reported in individuals with a personal or family history of an MH episode or central core disease but without sufficient information to consider the reports for informing PS4 (PMID:16835904). No functional studies were identified for this variant. This variant resides in a region of RYR1 considered to be a hotspot for pathogenic variants that contribute to MHS, PM1 (PMID: 21118704). A REVEL score >0.85 (0.886) supports a pathogenic status for this variant, PP3_Moderate. This variant has been classified as a Variant of Unknown Significance. Criteria implemented: PM1, PP3_Moderate. -

RYR1-related disorder Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Invitae

Mar 01, 2023

This missense change has been observed in individual(s) with autosomal dominant malignant hyperthermia and/or clinical features of autosomal dominant central core disease (PMID: 16835904, 35428369). This sequence change replaces arginine, which is basic and polar, with lysine, which is basic and polar, at codon 156 of the RYR1 protein (p.Arg156Lys). This variant is not present in population databases (gnomAD no frequency). ClinVar contains an entry for this variant (Variation ID: 133133). 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. 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. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.93
BayesDel_addAF	Pathogenic	0.51	D
BayesDel_noAF	Pathogenic	0.49
Cadd	Pathogenic	26
Dann	Benign	0.95
Eigen	Pathogenic	0.72
Eigen_PC	Uncertain	0.66
FATHMM_MKL	Uncertain	0.84	D
LIST_S2	Pathogenic	1.0	D;D
M_CAP	Pathogenic	0.49	D
MetaRNN	Pathogenic	0.97	D;D
MetaSVM	Pathogenic	1.1	D
MutationAssessor	Pathogenic	3.0	M;M
MutationTaster	Benign	0.98	D;D;D
PrimateAI	Pathogenic	0.82	D
PROVEAN	Uncertain	-2.4	N;N
REVEL	Pathogenic	0.89
Sift	Pathogenic	0.0	D;D
Polyphen		0.78	P;D
Vest4		0.75
MutPred		0.93		Gain of methylation at R156 (P = 0.0162);Gain of methylation at R156 (P = 0.0162);
MVP		1.0
MPC		1.0
ClinPred		0.98	D
GERP RS		4.3
Varity_R		0.67
gMVP		0.90

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs193922751; hg19: chr19-38934831;