19-38455489-T-C

Position:

• chr19-38455489-T-C

Variant summary

Our verdict is Likely pathogenic. Variant got 7 ACMG points: 7P and 0B. PM1 PP1 PS4_Moderate PP3_Moderate

This summary comes from the ClinGen Evidence Repository: 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 phenylalanine with leucine at codon 539 of the RYR1 protein, p.Phe539Leu. 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 individuals with a personal or family history of an MH episode, 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_Moderate (PMID:30236257, PMID:18564801 (reported two individuals, may be related with shared haplotype)). This variant segregates with MHS with three informative meiosis, PP1_Supporting (PMID:18564801). 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 (0.934) supports a pathogenic status for this variant, PP3_Moderate. This variant has been classified as a Variant of Unknown Significance. Criteria implemented: PS4_Moderate, PM1, PP1_Supporting, PP3_Moderate. LINK:https://erepo.genome.network/evrepo/ui/classification/CA024297/MONDO:0007783/012

• Frequency: Genomes: not found (cov: 31)
• Consequence: RYR1 NM_000540.3 missense
• Clinical Significance: Likely pathogenic reviewed by expert panel P:3 O:1
• Conservation: PhyloP100: 8.00

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 7 ACMG points.

• PS4: For more information check the summary or visit ClinGen Evidence Repository.
• PM1: For more information check the summary or visit ClinGen Evidence Repository.
• PP1: For more information check the summary or visit ClinGen Evidence Repository.
• PP3: For more information check the summary or visit ClinGen Evidence Repository.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
RYR1	NM_000540.3	c.1615T>C	p.Phe539Leu	missense_variant	15/106	ENST00000359596.8	NP_000531.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
RYR1	ENST00000359596.8	c.1615T>C	p.Phe539Leu	missense_variant	15/106	5	NM_000540.3	ENSP00000352608.2
RYR1	ENST00000355481.8	c.1615T>C	p.Phe539Leu	missense_variant	15/105	1		ENSP00000347667.3
RYR1	ENST00000599547.6	n.1615T>C		non_coding_transcript_exon_variant	15/80	2		ENSP00000471601.2

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome Cov.: 54

GnomAD4 genome Cov.: 31

ClinVar

Significance: Likely pathogenic

Submissions summary: Pathogenic:3 Other:1

Revision: reviewed by expert panel

Submissions by phenotype

Malignant hyperthermia, susceptibility to, 1 Pathogenic:2

Likely pathogenic, criteria provided, single submitter	clinical testing	Victorian Clinical Genetics Services, Murdoch Childrens Research Institute	Sep 23, 2024	Based on the classification scheme VCGS_Germline_v1.3.4, this variant is classified as Likely Pathogenic. Following criteria are met: 0103 - Loss of function and gain of function are known mechanisms of disease in this gene and are associated with RYR1-related disorders (OMIM). Gain of function mechanism has been described in the context of malignant hyperthermia susceptibility 1 (MIM#145600) and autosomal dominant congenital myopathy 1A with susceptibility to malignant hyperthermia (MIM#117000). Autosomal recessive congenital myopathy 1B (MIM#255320) is associated with a loss of function mechanism (PMIDs: 27855725, 23919265). The mechanism of King-Denborough syndrome (MIM#619542) is unclear. (I) 0108 - This gene is associated with both recessive and dominant disease (OMIM). (I) 0200 - Variant is predicted to result in a missense amino acid change from phenylalanine to leucine. (I) 0251 - This variant is heterozygous. (I) 0301 - Variant is absent from gnomAD (both v2 and v3). (SP) 0501 - Missense variant consistently predicted to be damaging by multiple in silico tools or highly conserved with a major amino acid change. (SP) 0602 - Variant is located in a hotspot region or cluster of pathogenic variants. Variants in this region are predominantly associated with MHS (PMID:23919265, PMID:30406384). (SP) 0704 - Another missense variant comparable to the one identified in this case has limited previous evidence for pathogenicity. p.(Phe539Val) has been classified as likely pathogenic by an expert panel (ClinVar). (SP) 0801 - This variant has strong previous evidence of pathogenicity in unrelated individuals. This variant has been identified in individuals with clinically confirmed malignant hyperthermia susceptibility (MHS) (PMID:18564801, PMID:30236257) and has been classified as likely pathogenic by an expert panel (ClinVar) and by the European Malignant Hyperthermia Group. (SP) 0901 - This variant has strong evidence for segregation with disease. This variant has shown to segregate in six individual’s from two unrelated families with positive IVCT results (Malignant Hyperthermia Diagnostic Unit, RMH). (SP) 1206 - This variant has been shown to be paternally inherited. (I) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign -
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 phenylalanine with leucine at codon 539 of the RYR1 protein, p.Phe539Leu. 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 individuals with a personal or family history of an MH episode, 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_Moderate (PMID:30236257, PMID:18564801 (reported two individuals, may be related with shared haplotype)). This variant segregates with MHS with three informative meiosis, PP1_Supporting (PMID:18564801). 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 (0.934) supports a pathogenic status for this variant, PP3_Moderate. This variant has been classified as a Variant of Unknown Significance. Criteria implemented: PS4_Moderate, PM1, PP1_Supporting, PP3_Moderate. -

RYR1-related disorder Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Jan 29, 2020

For these reasons, this variant has been classified as Pathogenic. This missense change is located in a region of the RYR1 protein where a significant number of previously reported RYR1 missense mutations are found (PMID: 16084090). These observations suggest that this may be a clinically significant region of the protein. 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. This variant has been observed in individual(s) with malignant hyperthermia (PMID: 18564801). ClinVar contains an entry for this variant (Variation ID: 133104). This variant is not present in population databases (ExAC no frequency). This sequence change replaces phenylalanine with leucine at codon 539 of the RYR1 protein (p.Phe539Leu). The phenylalanine residue is highly conserved and there is a small physicochemical difference between phenylalanine and leucine. -

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	1.0
BayesDel_addAF	Pathogenic	0.47	D
BayesDel_noAF	Pathogenic	0.44
CADD	Uncertain	25
DANN	Uncertain	0.99
DEOGEN2	Pathogenic	0.87	.;D
Eigen	Uncertain	0.65
Eigen_PC	Uncertain	0.58
FATHMM_MKL	Benign	0.14	N
LIST_S2	Pathogenic	1.0	D;D
M_CAP	Pathogenic	0.54	D
MetaRNN	Pathogenic	0.95	D;D
MetaSVM	Pathogenic	0.89	D
MutationAssessor	Uncertain	2.5	M;M
PrimateAI	Uncertain	0.75	T
PROVEAN	Pathogenic	-5.2	D;D
REVEL	Pathogenic	0.93
Sift	Uncertain	0.0020	D;D
Polyphen		1.0	D;D
Vest4		0.66
MutPred		0.86		Loss of catalytic residue at F539 (P = 0.1986);Loss of catalytic residue at F539 (P = 0.1986);
MVP		0.99
MPC		1.1
ClinPred		1.0	D
GERP RS		4.0
Varity_R		0.85
gMVP		0.85

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: rs193922769; hg19: chr19-38946129;