NM_000540.3:c.7291G>T

Variant names:

• chr19-38499984-G-T
• rs193922810
• NM_000540.3:c.7291G>T

Variant summary

Our verdict is Likely pathogenic. Variant got 9 ACMG points: 9P and 0B. PM5_Supporting PP1 PS3_Moderate PM1_Supporting 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 aspartic acid with tyrosine at codon 2431 of the RYR1 protein, p.(Asp2431Tyr). 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:30236257, PMID:30115273). Functional studies in HEK293 cells show an increased sensitivity to RYR1 agonists, PS3_Moderate (PMID:30115273). Another variant assessed as likely pathogenic occurs at this codon, p.(Asp2431Asn), PM5_Supporting. This variant resides in a region of RYR1 considered to be a hotspot for pathogenic variants that contribute to MHS, use PM1_Supporting to avoid overweighting with PM5 (PMID:21118704). This variant segregates with MHS in three individuals, PP1_Supporting (PMID:30236257). A REVEL score >0.85 (0.964) supports a pathogenic status for this variant, PP3_Moderate. This variant has been classified as Likely Pathogenic. Criteria implemented: PS4_Moderate, PS3_Moderate, PM1_Supporting, PM5_Supporting, PP1, PP3_Moderate. LINK:https://erepo.genome.network/evrepo/ui/classification/CA024744/MONDO:0007783/012

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 6.8e-7 (0 hom.)
• Consequence: RYR1 NM_000540.3 missense
• Clinical Significance: Likely pathogenic reviewed by expert panel P:6 O:1
• Conservation: PhyloP100: 9.98

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 9 ACMG points.

• PS3: For more information check the summary or visit ClinGen Evidence Repository.
• PS4: For more information check the summary or visit ClinGen Evidence Repository.
• PM1: For more information check the summary or visit ClinGen Evidence Repository.
• PM5: 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 rank	MANE	Protein	UniProt
RYR1	NM_000540.3	c.7291G>T	p.Asp2431Tyr	missense_variant	Exon 45 of 106	ENST00000359596.8	NP_000531.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
RYR1	ENST00000359596.8	c.7291G>T	p.Asp2431Tyr	missense_variant	Exon 45 of 106	5	NM_000540.3	ENSP00000352608.2
RYR1	ENST00000355481.8	c.7291G>T	p.Asp2431Tyr	missense_variant	Exon 45 of 105	1		ENSP00000347667.3
RYR1	ENST00000594335.5	n.742G>T		non_coding_transcript_exon_variant	Exon 6 of 49	1		ENSP00000470927.2
RYR1	ENST00000599547.6	n.7291G>T		non_coding_transcript_exon_variant	Exon 45 of 80	2		ENSP00000471601.2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 6.84e-7 AC: 1 AN: 1461834 Hom.: 0 Cov.: 36 AF XY: 0.00000138 AC XY: 1 AN XY: 727220

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000116

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

ClinVar

Significance: Likely pathogenic

Submissions summary: Pathogenic:6 Other:1

Revision: reviewed by expert panel

Submissions by phenotype

Malignant hyperthermia, susceptibility to, 1 Pathogenic:3

Mar 30, 2023

Molecular Genetics, Royal Melbourne Hospital

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change is predicted to replace aspartic acid with tyrosine at codon 2431 of the RYR1 protein (p.(Asp2431Tyr)). The aspartic acid residue is invariant across species (100 vertebrates, UCSC), and there is a large physicochemical difference between aspartic acid and tyrosine. The variant is absent in a large population cohort (gnomAD v2.1 and v3.0). The prevalence of the variant in an affected cohort is significantly increased compared with the prevalence of a relevant low risk population (PMID: 30236257). The variant is associated with a clinical reaction consistent with malignant hyperthermia (MH) under anaesthesia and confirmed by a positive in vitro contracture tests, and segregates with MH susceptibility in multiple families (PMID: 19648156, 30115273, 30236257). A well-established in vitro functional study is supportive of a gain of function effect on intracellular calcium release for the variant (PMID: 30115273). Multiple lines of computational evidence predict a deleterious effect for the missense substitution (5/5 algorithms). Based on the classification scheme RMH ACMG Guidelines v1.2.1, this variant is classified as PATHOGENIC. Following criteria are met: PS3, PS4, PM2, PP1, PP3, PP4. -

Sep 20, 2024

Victorian Clinical Genetics Services, Murdoch Childrens Research Institute

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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 aspartic acid to tyrosine. (I) 0251 - This variant is heterozygous. (I) 0301 - Variant is absent from gnomAD (both v2 and v3). (SP) 0309 - An alternative amino acid change at the same position has been observed in gnomAD (v3: 3 heterozygotes, 0 homozygotes). (I) 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 (PMID: 33767344). (SP) 0704 - Another missense variant comparable to the one identified in this case has limited previous evidence for pathogenicity. p.(Asp2431Asn) has been reported as likely pathogenic by the ClinGen Malignant Hyperthermia Susceptibility Variant Curation Expert Panel and two other clinical laboratories, and as a VUS by one clinical laboratory (ClinVar). In addition, p.(Asp2431Val) has been reported in a family with malignant hyperthermia (PMID: 30236257), and as a VUS by the ClinGen Malignant Hyperthermia Susceptibility Variant Curation Expert Panel (ClinVar). (SP) 0801 - This variant has strong previous evidence of pathogenicity in unrelated individuals. It has been listed as a diagnostic MH pathogenic variant by the European Malignant Hyperthermia Group, and as likely pathogenic by the ClinGen Malignant Hyperthermia Susceptibility Variant Curation Expert Panel (ClinVar). It has also been reported as likely pathogenic/pathogenic by several clinical testing laboratories (ClinVar). This variant has been reported in three unrelated UK families with malignant hyperthermia (PMID: 30236257). (SP) 0906 - Segregation evidence for this variant is inconclusive. Several family members of this individual had been tested for the variant; however, the variant was not shown to definitively segregate with a positive IVCT result (PMID: 30115273). (I) 1002 - This variant has moderate functional evidence supporting abnormal protein function. Functional study showed HEK293 cells with this variant exhibited hypersensitivity to an RYR1 agonist (PMID: 30115273). (SP) 1208 - Inheritance information for this variant is not currently available in this individual. (I) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign -

Apr 07, 2023

ClinGen Malignant Hyperthermia Susceptibility Variant Curation Expert Panel, ClinGen

Significance: Likely pathogenic

Review Status: reviewed by expert panel

Collection Method: curation

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 aspartic acid with tyrosine at codon 2431 of the RYR1 protein, p.(Asp2431Tyr). 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:30236257, PMID:30115273). Functional studies in HEK293 cells show an increased sensitivity to RYR1 agonists, PS3_Moderate (PMID:30115273). Another variant assessed as likely pathogenic occurs at this codon, p.(Asp2431Asn), PM5_Supporting. This variant resides in a region of RYR1 considered to be a hotspot for pathogenic variants that contribute to MHS, use PM1_Supporting to avoid overweighting with PM5 (PMID: 21118704). This variant segregates with MHS in three individuals, PP1_Supporting (PMID:30236257). A REVEL score >0.85 (0.964) supports a pathogenic status for this variant, PP3_Moderate. This variant has been classified as Likely Pathogenic. Criteria implemented: PS4_Moderate, PS3_Moderate, PM1_Supporting, PM5_Supporting, PP1, PP3_Moderate. -

not provided Pathogenic:1 Other:1

-

RYR1 database

Significance: not provided

Review Status: no classification provided

Collection Method: literature only

- -

Apr 14, 2022

GeneDx

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Not observed at significant frequency in large population cohorts (gnomAD); Published functional studies suggest the variant caused an increased sensitivity to RYR1 agonists (Scheimann et al., 2018); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 19648156, 16917943, 12668474, 30115273, 30236257) -

RYR1-related disorder Pathogenic:1

Jan 06, 2020

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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 variant disrupts the p.Asp2431 amino acid residue in RYR1. Other variant(s) that disrupt this residue have been observed in individuals with RYR1-related conditions (PMID: 11575529, 15448513, 16917943, 30236257), which suggests that this may be a clinically significant amino acid residue. This variant has been observed in individual(s) with malignant hyperthermia susceptibility (PMID: 16917943, 19648156, 30236257). ClinVar contains an entry for this variant (Variation ID: 133195). This variant is not present in population databases (ExAC no frequency). This sequence change replaces aspartic acid with tyrosine at codon 2431 of the RYR1 protein (p.Asp2431Tyr). The aspartic acid residue is highly conserved and there is a large physicochemical difference between aspartic acid and tyrosine. -

Congenital myopathy with fiber type disproportion Pathogenic:1

Jan 02, 2019

Centre for Mendelian Genomics, University Medical Centre Ljubljana

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant was classified as: Likely pathogenic. The following ACMG criteria were applied in classifying this variant: PM2,PM5,PP2,PP3,PP5. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.98
BayesDel_addAF	Pathogenic	0.56	D
BayesDel_noAF	Pathogenic	0.57
CADD	Uncertain	25
DANN	Benign	0.93
DEOGEN2	Pathogenic	0.87	.;D
Eigen	Uncertain	0.66
Eigen_PC	Uncertain	0.55
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.95	D;D
M_CAP	Pathogenic	0.88	D
MetaRNN	Pathogenic	0.99	D;D
MetaSVM	Pathogenic	1.0	D
MutationAssessor	Uncertain	2.6	M;M
PrimateAI	Pathogenic	0.90	D
PROVEAN	Pathogenic	-8.4	D;D
REVEL	Pathogenic	0.96
Sift	Pathogenic	0.0	D;D
Polyphen		1.0	D;D
Vest4		0.91
MutPred		0.88		Gain of catalytic residue at I2430 (P = 0.0608);Gain of catalytic residue at I2430 (P = 0.0608);
MVP		1.0
MPC		0.52
ClinPred		1.0	D
GERP RS		4.0
Varity_R		0.95
gMVP		0.98

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: rs193922810; hg19: chr19-38990624;