rs118192123

chr19-38500640-T-C

Variant summary

Our verdict is Pathogenic. Variant got 15 ACMG points: 15P and 0B. PM1 PM2 PP2 PP3_Moderate PP5_Very_Strong

The NM_000540.3(RYR1):c.7358T>C(p.Ile2453Thr) 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 Likely pathogenic (★★★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: RYR1 NM_000540.3 missense
• Clinical Significance: Likely pathogenic reviewed by expert panel P:4 O:1
• Conservation: PhyloP100: 8.01

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 15 ACMG points.

• PM1: In a hotspot region, there are 4 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 1 benign, 9 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, 0.915
• PP5: Variant 19-38500640-T-C is Pathogenic according to our data. Variant chr19-38500640-T-C is described in ClinVar as [Likely_pathogenic]. Clinvar id is 65953.Status of the report is reviewed_by_expert_panel, 3 stars. Variant chr19-38500640-T-C is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
RYR1	NM_000540.3	c.7358T>C	p.Ile2453Thr	missense_variant	46/106	ENST00000359596.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
RYR1	ENST00000359596.8	c.7358T>C	p.Ile2453Thr	missense_variant	46/106	5	NM_000540.3	A2
RYR1	ENST00000355481.8	c.7358T>C	p.Ile2453Thr	missense_variant	46/105	1		P4
RYR1	ENST00000594335.5	c.812T>C	p.Ile271Thr	missense_variant, NMD_transcript_variant	7/49	1
RYR1	ENST00000599547.6	c.7358T>C	p.Ile2453Thr	missense_variant, NMD_transcript_variant	46/80	2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

ClinVar

Significance: Likely pathogenic

Submissions summary: Pathogenic:4 Other:1

Revision: reviewed by expert panel

Submissions by phenotype

Central core myopathy Pathogenic:2

Pathogenic, no assertion criteria provided	curation	GeneReviews	May 11, 2010	- -
Pathogenic, criteria provided, single submitter	clinical testing	Institute of Human Genetics Munich, Klinikum Rechts Der Isar, TU München	Nov 08, 2019	- -

RYR1-related disorder Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Invitae

Sep 15, 2020

This variant is not present in population databases (ExAC no frequency). This variant has been observed in individual(s) with central core disease (PMID: 14708096, Invitae) and malignant hyperthermia susceptibility (PMID: 12434264, 14708096). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 65953). 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. For these reasons, this variant has been classified as Pathogenic. This sequence change replaces isoleucine with threonine at codon 2453 of the RYR1 protein (p.Ile2453Thr). The isoleucine residue is highly conserved and there is a moderate physicochemical difference between isoleucine and threonine. -

Malignant hyperthermia, susceptibility to, 1 Pathogenic:1

Likely pathogenic, 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 isoleucine with threonine at codon 2453 of the RYR1 protein, p.(Ile2453Thr). This variant was not present in a large population database (gnomAD) at the time it was interpreted. This variant has been reported in an individual with a personal history of an MH episode and a positive in vitro contracture test (IVCT), PS4_Supporting (PMID:12434264). The mother was positive for the variant and was determined to be IVCT positive, and the variant was determined to be de novo in the mother with confirmed parentage, PS2_Moderate. A functional study using sarcoplasmic reticulum membrane vesicles was published for this variant; this assay is not considered a standard assay by the ClinGen RYR1 VCEP for MHS and PS3 was not applied (PMID:16958617). 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 (0.891) supports a pathogenic status for this variant, PP3_Moderate. This variant has been classified as Likely Pathogenic. Criteria implemented: PS2_Moderate, PS4_Supporting, PM1, PP3_Moderate. -

not provided Other:1

not provided, no classification provided

literature only

Leiden Muscular Dystrophy (RYR1)

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Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.99
BayesDel_addAF	Pathogenic	0.51	D
BayesDel_noAF	Pathogenic	0.49
Cadd	Uncertain	24
Dann	Uncertain	0.99
Eigen	Uncertain	0.21
Eigen_PC	Uncertain	0.27
FATHMM_MKL	Uncertain	0.97	D
LIST_S2	Pathogenic	0.99	D;D
M_CAP	Uncertain	0.26	D
MetaRNN	Pathogenic	0.91	D;D
MetaSVM	Uncertain	0.79	D
MutationAssessor	Uncertain	2.4	M;M
MutationTaster	Benign	1.0	D;D;D
PrimateAI	Pathogenic	0.90	D
PROVEAN	Uncertain	-4.3	D;D
REVEL	Pathogenic	0.89
Sift	Uncertain	0.017	D;D
Polyphen		0.59	P;P
Vest4		0.82
MutPred		0.84		Loss of stability (P = 0.0072);Loss of stability (P = 0.0072);
MVP		0.99
MPC		0.38
ClinPred		0.99	D
GERP RS		4.0
Varity_R		0.46
gMVP		0.78

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: rs118192123; hg19: chr19-38991280;