rs112596687

Positions:

• chr19-38446517-T-A
• chr19-38446517-T-C
• chr19-38446517-T-G

Variant summary

Our verdict is Uncertain significance. Variant got 4 ACMG points: 4P and 0B. PS4_Moderate PM1

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 methionine with lysine at codon 226 of the RYR1 protein, p.(Met226Lys). 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, three 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:24433488, PMID:30236257). 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 of 0.841 supports neither a pathogenic nor a benign status for this variant. This variant has been classified as a Variant of Unknown Significance. Criteria implemented: PS4_Moderate, PM1. LINK:https://erepo.genome.network/evrepo/ui/classification/CA024646/MONDO:0007783/012

• Frequency: Genomes: not found (cov: 32)
• Consequence: RYR1 NM_000540.3 missense
• Clinical Significance: Uncertain significance reviewed by expert panel U:2 O:1
• Conservation: PhyloP100: 5.33

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 Uncertain_significance. Variant got 4 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.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
RYR1	NM_000540.3	c.677T>A	p.Met226Lys	missense_variant	8/106	ENST00000359596.8	NP_000531.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
RYR1	ENST00000359596.8	c.677T>A	p.Met226Lys	missense_variant	8/106	5	NM_000540.3	ENSP00000352608	A2
RYR1	ENST00000355481.8	c.677T>A	p.Met226Lys	missense_variant	8/105	1		ENSP00000347667	P4
RYR1	ENST00000599547.6	c.677T>A	p.Met226Lys	missense_variant, NMD_transcript_variant	8/80	2		ENSP00000471601

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:2 Other:1

Revision: reviewed by expert panel

Submissions by phenotype

RYR1-related disorder Uncertain:1

Uncertain significance, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

May 23, 2024

The RYR1 c.677T>A variant is predicted to result in the amino acid substitution p.Met226Lys. This variant has been reported in two individuals with malignant hyperthermia, but no additional studies were done to assess its pathogenicity (Robinson et al. 2006. PubMed ID: 16917943; Miller et al. 2018. PubMed ID: 30236257). This variant has not been reported in a large population database, indicating this variant is rare. This variant is interpreted as uncertain by a ClinGen Expert Panel in ClinVar (https://www.ncbi.nlm.nih.gov/clinvar/variation/133170/). At this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence. -

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 methionine with lysine at codon 226 of the RYR1 protein, p.(Met226Lys). 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, three 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:24433488, PMID:30236257). 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 of 0.841 supports neither a pathogenic nor a benign status for this variant. This variant has been classified as a Variant of Unknown Significance. Criteria implemented: PS4_Moderate, PM1. -

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	0.66
BayesDel_addAF	Pathogenic	0.40	D
BayesDel_noAF	Pathogenic	0.33
CADD	Uncertain	24
DANN	Benign	0.94
DEOGEN2	Uncertain	0.62	.;D
Eigen	Uncertain	0.67
Eigen_PC	Uncertain	0.64
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Uncertain	0.91	D;D
M_CAP	Uncertain	0.19	D
MetaRNN	Pathogenic	0.94	D;D
MetaSVM	Uncertain	0.52	D
MutationAssessor	Uncertain	2.5	M;M
MutationTaster	Benign	1.0	D;D;D
PrimateAI	Pathogenic	0.79	T
PROVEAN	Uncertain	-2.7	D;D
REVEL	Pathogenic	0.84
Sift	Benign	0.048	D;D
Polyphen		0.99	D;D
Vest4		0.90
MutPred		0.83		Gain of ubiquitination at M226 (P = 0.03);Gain of ubiquitination at M226 (P = 0.03);
MVP		0.94
MPC		1.2
ClinPred		0.99	D
GERP RS		5.0
Varity_R		0.73
gMVP		0.74

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: rs112596687; hg19: chr19-38937157;