rs118192151

Positions:

Variant summary

Our verdict is Uncertain significance. Variant got 3 ACMG points: 3P and 0B. PM1_SupportingPP3_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 arginine with glutamine at codon 4893 of the RYR1 protein, p.(Arg4893Gln). This variant was not present in a large population database (gnomAD) at the time this variant was interpreted. To our knowledge this variant has not been reported in the literature in individuals who have a personal or family history of a malignant hyperthermia reaction (PMID:30236257, UK (Leeds) MH Investigational Unit). 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_Supporting (PMID:21118704). A REVEL score >0.85 (0.963) supports a pathogenic status for this variant, PP3_Moderate. This variant has been classified as a Variant of Uncertain Significance. Criteria implemented: PM1_Supporting, PP3_Moderate. LINK:https://erepo.genome.network/evrepo/ui/classification/CA024221/MONDO:0018493/012

Frequency

Genomes: not found (cov: 29)

Consequence

RYR1
NM_000540.3 missense

Scores

Clinical Significance

Uncertain significance reviewed by expert panel P:9U:1O:1

Conservation

PhyloP100: 10.0

Variant links:

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]

RYR1 links:

RYR1 (HGNC:):

RYR1 links:

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ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 3 ACMG points.

PM1

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 linkuse as main transcript	c.14678G>A	p.Arg4893Gln	missense_variant	102/106	ENST00000359596.8	NP_000531.2	P21817-1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
RYR1	ENST00000359596.8 linkuse as main transcript	c.14678G>A	p.Arg4893Gln	missense_variant	102/106	5	NM_000540.3	ENSP00000352608.2		P21817-1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

Cov.:

GnomAD4 genome

Cov.:

ClinVar

Significance: Uncertain significance

Submissions summary: Pathogenic:9Uncertain:1Other:1

Revision: reviewed by expert panel

LINK: link

Submissions by phenotype

not provided

Pathogenic:5Other:1

Pathogenic, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	Oct 14, 2016	- -
not provided, no classification provided	literature only	Leiden Muscular Dystrophy (RYR1)	-	- -
Likely pathogenic, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Aug 01, 2024	RYR1: PM1, PM2, PM5, PS4:Moderate, PP3 -
Pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Mar 13, 2024	Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; In silico analysis supports a deleterious effect on splicing; This variant is associated with the following publications: (PMID: 11709545, 20301565, 25331388, 12565913, 23183335, 25214167, 15564033, 22550088, 35693006, 31130284, 25628744, 16917943, 35081925, 17483490, 33646171, 29669168, 20681998, 33767344, 30236257) -
Likely pathogenic, criteria provided, single submitter	clinical testing	Genetic Services Laboratory, University of Chicago	Mar 04, 2016	- -
Likely pathogenic, criteria provided, single submitter	clinical testing	Revvity Omics, Revvity	Jun 14, 2023	- -

RYR1-related disorder

Pathogenic:2

Pathogenic, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Mar 24, 2022	Variant summary: RYR1 c.14678G>A (p.Arg4893Gln) results in a conservative amino acid change located in the Ion transport domain (IPR005821) of the encoded protein sequence. Four of five in-silico tools predict a damaging effect of the variant on protein function. The variant was absent in 282656 control chromosomes (gnomAD and publication data). c.14678G>A has been reported in the literature in multiple individuals affected with Central Core Disease and Malignant Hyperthermia Susceptibility (e.g. Davis_2003, Chang_2013, Kraeva_2013, Jung_2015, Miller_2018). In addition, this variant was co-segregated with disease in at least two unrelative families (Chang_2013, Miller_2018). These data indicate that the variant is very likely to be associated with disease. Experimental evidence evaluating an impact on protein function showed that equivalent mutations in rabbit RYR1 has equivalent Ca2+ signaling activity as an RYR1 null control in a cell transfection assay (Kraeva_2013) and showed 60% reduction in voltage sensitivity when assayed via electrophysiology (Kraeva_2013). Different missense substitutions at this codon (R4893P, R4893W) were reported in individuals affected with Central core disease in HGMD database (PMID: 16621918, 11709545). This suggests that the arginine residue is critical for RYR1 protein function and that other missense substitutions at this position may also be pathogenic (R4893P and R4893W have been classified as pathogenic in ClinVar database). Six ClinVar submitters, including one expert panel, has assessed the variant since 2014: the variant was classified as of uncertain significance by the expert panel, as likely pathogenic by one laboratory, and pathogenic by four laboratories. Based on the evidence outlined above, the variant was classified as pathogenic. -
Pathogenic, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 02, 2024	This sequence change replaces arginine, which is basic and polar, with glutamine, which is neutral and polar, at codon 4893 of the RYR1 protein (p.Arg4893Gln). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individuals with autosomal dominant malignant hyperthermia and central core disease (CCD) (PMID: 12565913, 22550088, 23183335, 25628744, 30236257). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 65988). 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 with a positive predictive value of 95%. Experimental studies have shown that this missense change affects RYR1 function (PMID: 23183335). This variant disrupts the p.Arg4893 amino acid residue in RYR1. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 11709545, 14670767). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. For these reasons, this variant has been classified as Pathogenic. -

Inborn genetic diseases

Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

Ambry Genetics

Nov 30, 2023

The c.14678G>A (p.R4893Q) alteration is located in exon 102 (coding exon 102) of the RYR1 gene. This alteration results from a G to A substitution at nucleotide position 14678, causing the arginine (R) at amino acid position 4893 to be replaced by a glutamine (Q)._x000D_ _x000D_ for autosomal dominant RYR1-related myopathy; however, its clinical significance for autosomal dominant malignant hyperthermia susceptibility is uncertain. This variant was not reported in population-based cohorts in the Genome Aggregation Database (gnomAD). This variant has been reported in the heterozygous state in multiple individuals with central core disease or other clinical symptoms of RYR1-related myopathy (Zhou, 2007; Kraeva, 2013; Savarese, 2014; Jung, 2015; Todd, 2018; Monies, 2019; Chang, 2022). It has been observed to segregate with disease in one family with central core disease (Chang, 2013). Additionally, this variant has also been observed in three unrelated families with malignant hyperthermia susceptibility (Miller, 2018). Another alteration at the same codon, c.14677C>T (p.R4893W), has been reported in individuals with clinical features consistent with RYR1-related myopathy (Monnier, 2001; Quinlivan, 2003). This amino acid position is highly conserved in available vertebrate species. This alteration is predicted to be deleterious by in silico analysis. Based on the available evidence, this alteration is classified as likely pathogenic. -

Central core myopathy

Pathogenic:1

Pathogenic, no assertion criteria provided

curation

GeneReviews

May 11, 2010

- -

Malignant hyperthermia of anesthesia

Uncertain:1

Uncertain significance, 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 arginine with glutamine at codon 4893 of the RYR1 protein, p.(Arg4893Gln). This variant was not present in a large population database (gnomAD) at the time this variant was interpreted. To our knowledge this variant has not been reported in the literature in individuals who have a personal or family history of a malignant hyperthermia reaction (PMID:30236257, UK (Leeds) MH Investigational Unit). 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_Supporting (PMID: 21118704). A REVEL score >0.85 (0.963) supports a pathogenic status for this variant, PP3_Moderate. This variant has been classified as a Variant of Uncertain Significance. Criteria implemented: PM1_Supporting, PP3_Moderate. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.99

BayesDel_addAF

Pathogenic

0.53

BayesDel_noAF

Pathogenic

0.53

CADD

Pathogenic

DANN

Uncertain

0.99

DEOGEN2

Pathogenic

0.94

.;D

Eigen

Pathogenic

0.99

Eigen_PC

Pathogenic

0.92

FATHMM_MKL

Pathogenic

1.0

LIST_S2

Pathogenic

1.0

D;D

M_CAP

Pathogenic

0.83

MetaRNN

Pathogenic

0.98

D;D

MetaSVM

Pathogenic

1.1

MutationAssessor

Pathogenic

3.5

.;M

PrimateAI

Pathogenic

0.84

PROVEAN

Uncertain

-3.3

D;D

REVEL

Pathogenic

0.96

Sift

Pathogenic

0.0

D;D

Polyphen

1.0

D;D

Vest4

0.91

MutPred

0.87

.;Loss of methylation at R4893 (P = 0.0194);

MVP

1.0

MPC

0.78

ClinPred

1.0

GERP RS

5.1

Varity_R

0.94

gMVP

1.0

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.58

Details are displayed if max score is > 0.2

DS_AG_spliceai

0.58

Position offset: 2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over