rs193922744

chr19-38433867-T-G

Variant summary

Our verdict is Pathogenic. Variant got 17 ACMG points: 17P and 0B. PM2 PM5 PP2 PP3_Strong PP5_Very_Strong

The NM_000540.3(RYR1):c.38T>G(p.Leu13Arg) variant causes a missense change. 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 (★★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. L13V) has been classified as Likely pathogenic.

• Frequency: Genomes: not found (cov: 30)
• Consequence: RYR1 NM_000540.3 missense
• Clinical Significance: Likely pathogenic reviewed by expert panel P:4 U:1 O:1
• Conservation: PhyloP100: 4.24

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 17 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PM5: Other missense variant is known to change same aminoacid residue: Variant chrnull-null-null-null is described in UniProt as null.
• PP2: Missense variant where missense usually causes diseases, RYR1
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.99
• PP5: Variant 19-38433867-T-G is Pathogenic according to our data. Variant chr19-38433867-T-G is described in ClinVar as [Likely_pathogenic]. Clinvar id is 133129.Status of the report is reviewed_by_expert_panel, 3 stars. Variant chr19-38433867-T-G is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
RYR1	NM_000540.3	c.38T>G	p.Leu13Arg	missense_variant	1/106	ENST00000359596.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
RYR1	ENST00000359596.8	c.38T>G	p.Leu13Arg	missense_variant	1/106	5	NM_000540.3	A2
RYR1	ENST00000355481.8	c.38T>G	p.Leu13Arg	missense_variant	1/105	1		P4
RYR1	ENST00000599547.6	c.38T>G	p.Leu13Arg	missense_variant, NMD_transcript_variant	1/80	2

Frequencies

GnomAD3 genomes Cov.: 30

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 30

ClinVar

Significance: Likely pathogenic

Submissions summary: Pathogenic:4 Uncertain:1 Other:1

Revision: reviewed by expert panel

Submissions by phenotype

not provided Pathogenic:1 Uncertain:1 Other:1

Uncertain significance, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	Jul 14, 2015	- -
Likely pathogenic, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Jun 28, 2023	The RYR1 c.38T>G; p.Leu13Arg variant (rs193922744) is reported in the literature in individuals affected with malignant hyperthermia susceptibility (Brandom 2013, Ibarra 2006, Levano 2009, Robinson 2006, Snoeck 2015, van den Bersselaar 2021) and is also reported in ClinVar (Variation ID: 133129). Additionally, in vitro functional analyses in HEK293 cells demonstrate hypersensitivity to RYR1 agonists (van den Bersselaar 2021). This variant is absent from the Genome Aggregation Database, indicating it is not a common polymorphism. Computational analyses are uncertain whether this variant is neutral or deleterious (REVEL: 0.828). Based on available information, this variant is considered to be likely pathogenic. References: Brandom BW et al. Ryanodine receptor type 1 gene variants in the malignant hyperthermia-susceptible population of the United States. Anesth Analg. 2013 May;116(5):1078-1086. PMID: 23558838. Ibarra M CA et al. Malignant hyperthermia in Japan: mutation screening of the entire ryanodine receptor type 1 gene coding region by direct sequencing. Anesthesiology. 2006 Jun;104(6):1146-54. PMID: 16732084. Levano S et al. Increasing the number of diagnostic mutations in malignant hyperthermia. Hum Mutat. 2009 Apr;30(4):590-8. PMID: 19191329. Robinson R et al. Mutations in RYR1 in malignant hyperthermia and central core disease. Hum Mutat. 2006 Oct;27(10):977-89. PMID: 16917943. Snoeck M et al. RYR1-related myopathies: a wide spectrum of phenotypes throughout life. Eur J Neurol. 2015 Jul;22(7):1094-112. PMID: 25960145. van den Bersselaar LR et al. RYR1 variant c.38T>G, p.Leu13Arg causes hypersensitivity of the ryanodine receptor-1 and is pathogenic for malignant hyperthermia. Br J Anaesth. 2021 Aug;127(2):e63-e65. PMID: 34127251. -
not provided, no classification provided	literature only	Leiden Muscular Dystrophy (RYR1)	-	- -

Malignant hyperthermia, susceptibility to, 1 Pathogenic:2

Likely pathogenic, criteria provided, single submitter	clinical testing	Institute of Human Genetics, University of Leipzig Medical Center	Mar 26, 2024	Criteria applied: PS3_MOD,PS4_MOD,PM1,PP1 -
Likely pathogenic, reviewed by expert panel	curation	ClinGen Malignant Hyperthermia Susceptibility Variant Curation Expert Panel, ClinGen	Apr 07, 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 leucine with arginine at codon 13 of the RYR1 protein, p.(Leu13Arg). This variant was not present in a large population database (gnomAD) at the time this variant was interpreted. This variant has been reported in three unrelated individuals who have a personal or family history of a malignant hyperthermia reaction, two 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_Moderate (PMID:19191329; PMID:30236257; PMID:16732084). Functional studies in HEK293 cells show an increased sensitivity to RYR1 agonists, PS3_Moderate (PMID: 341427251). 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 three individuals ,PP1 (PMID:19191329, personal communication, RYR1/MHS_VCEP). A REVEL score of 0.828 supports neither a pathogenic nor a benign status for this variant. This variant has been classified as Likely Pathogenic. Criteria implemented: PS3_Moderate, PS4_Moderate, PM1, PP1. -

RYR1-related disorder Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Invitae

Apr 17, 2023

For these reasons, this variant has been classified as Pathogenic. Experimental studies have shown that this missense change affects RYR1 function (PMID: 34127251). 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. ClinVar contains an entry for this variant (Variation ID: 133129). This missense change has been observed in individual(s) with malignant hyperthermia and/or malignant hyperthermia susceptibility (PMID: 16917943, 19191329, 23558838, 25960145, 34127251). It has also been observed to segregate with disease in related individuals. This variant is not present in population databases (gnomAD no frequency). This sequence change replaces leucine, which is neutral and non-polar, with arginine, which is basic and polar, at codon 13 of the RYR1 protein (p.Leu13Arg). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.91
BayesDel_addAF	Pathogenic	0.53	D
BayesDel_noAF	Pathogenic	0.53
Cadd	Uncertain	25
Dann	Uncertain	0.99
Eigen	Uncertain	0.64
Eigen_PC	Uncertain	0.58
FATHMM_MKL	Uncertain	0.83	D
LIST_S2	Pathogenic	0.99	D;D
M_CAP	Pathogenic	0.43	D
MetaRNN	Pathogenic	0.99	D;D
MetaSVM	Pathogenic	1.1	D
MutationAssessor	Uncertain	2.7	M;M
MutationTaster	Benign	0.74	D;D;D
PrimateAI	Pathogenic	0.85	D
PROVEAN	Uncertain	-3.6	D;D
REVEL	Pathogenic	0.83
Sift	Uncertain	0.0010	D;D
Polyphen		1.0	D;D
Vest4		0.86
MutPred		0.97		Gain of disorder (P = 0.0116);Gain of disorder (P = 0.0116);
MVP		0.98
MPC		1.3
ClinPred		1.0	D
GERP RS		4.8
Varity_R		0.89
gMVP		0.95

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: rs193922744; hg19: chr19-38924507;