chr19-38504319-C-T

Variant names:

• chr19-38504319-C-T
• rs193922826
• NM_000540.3:c.8026C>T

Variant summary

Our verdict is Likely pathogenic. Variant got 6 ACMG points: 6P and 0B. PS4_Moderate PP1_Strong

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 tryptophan at codon 2676 of the RYR1 protein, p.(Arg2676Trp). The maximum allele frequency for this variant among the six major gnomAD populations is NFE: 0.0000259, a frequency consistent with pathogenicity for MHS. This variant has been reported in eight unrelated individuals who have a personal or family history of a malignant hyperthermia reaction, 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). Two individuals were reported to have a second variant in RYR1 and were not considered for PS4, PS4_Moderate was applied (PMID:30236257, PMID:16163667, PMID:19191329, PMID:25960145, PMID:21157159, Stowell Laboratory personal communication). No functional studies were identified for this variant. This variant does not reside in a hotspot for pathogenic variants that contribute to MHS. This variant segregates with MHS in more than ten individuals, PP1_Strong (PMID:30236257, PMID:25960145, PMID:14732627). A REVEL score of 0.601 supports neither a pathogenic nor a benign status for this variant. This variant has been classified as a Likely Pathogenic. Criteria implemented: PS4_Moderate, PP1_Strong. LINK:https://erepo.genome.network/evrepo/ui/classification/CA024883/MONDO:0018493/012

• Frequency:
  • Genomes: 𝑓 0.000013 (0 hom., cov: 31)
  • Exomes 𝑓: 0.0000027 (0 hom.)
• Consequence: RYR1 NM_000540.3 missense
• Clinical Significance: Likely pathogenic reviewed by expert panel P:4 U:2 O:1
• Conservation: PhyloP100: 1.02

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 6 ACMG points.

• PS4: For more information check the summary or visit ClinGen Evidence Repository.
• PP1: 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.8026C>T	p.Arg2676Trp	missense_variant	Exon 50 of 106	ENST00000359596.8	NP_000531.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
RYR1	ENST00000359596.8	c.8026C>T	p.Arg2676Trp	missense_variant	Exon 50 of 106	5	NM_000540.3	ENSP00000352608.2
RYR1	ENST00000355481.8	c.8026C>T	p.Arg2676Trp	missense_variant	Exon 50 of 105	1		ENSP00000347667.3
RYR1	ENST00000594335.5	n.1477C>T		non_coding_transcript_exon_variant	Exon 11 of 49	1		ENSP00000470927.2
RYR1	ENST00000599547.6	n.8026C>T		non_coding_transcript_exon_variant	Exon 50 of 80	2		ENSP00000471601.2

Frequencies

GnomAD3 genomes AF: 0.0000131 AC: 2 AN: 152166 Hom.: 0 Cov.: 31

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000294

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.0000119 AC: 3 AN: 251366 Hom.: 0 AF XY: 0.00000736 AC XY: 1 AN XY: 135874

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000264

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000274 AC: 4 AN: 1461890 Hom.: 0 Cov.: 34 AF XY: 0.00000138 AC XY: 1 AN XY: 727248

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: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000360

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome AF: 0.0000131 AC: 2 AN: 152166 Hom.: 0 Cov.: 31 AF XY: 0.0000135 AC XY: 1 AN XY: 74312

Gnomad4 AFR AF: 0.00

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000294

Gnomad4 OTH AF: 0.00

Bravo AF: 0.00000378

ExAC AF: 0.00000824 AC: 1

ClinVar

Significance: Likely pathogenic

Submissions summary: Pathogenic:4 Uncertain:2 Other:1

Revision: reviewed by expert panel

Submissions by phenotype

not provided Uncertain:2 Other:1

-

RYR1 database

Significance: not provided

Review Status: no classification provided

Collection Method: literature only

- -

Dec 02, 2013

Genetic Services Laboratory, University of Chicago

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Aug 01, 2020

CeGaT Center for Human Genetics Tuebingen

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Malignant hyperthermia, susceptibility to, 1 Pathogenic:2

Jan 20, 2022

MGZ Medical Genetics Center

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Feb 07, 2024

All of Us Research Program, National Institutes of Health

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.8026C>T (p.Arg2676Trp) variant of the RYR1 gene replaces arginine with tryptophan at codon 2676 of the RYR1 protein. This variant has been reported in six unrelated individuals who have a personal or family history of a malignant hyperthermia reaction, a positive in vitro contracture test (IVCT) or caffeine halothane contracture test (CHCT) results (PMID:14732627, 30236257, 16163667, 19191329, 25960145, 21157159). This variant has been identified in an unaffected individual (PMID: 21157159). This variant has been shown to segregate with malignant hyperthermia syndrome (MHS) in more than 10 individuals (PMID: 30236257, 25960145, 14732627). No functional study was identified for this variant. This variant does not reside in a hotspot for pathogenic variants that contribute to MHS. Computational prediction suggests that this variant may not have deleterious impact on protein structure and function (REVEL score 0.601). Therefore, this c.8026C>T (p.Arg2676Trp) variant of the RYR1 gene is classified as likely pathogenic. -

RYR1-related disorder Pathogenic:1

Apr 24, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change replaces arginine, which is basic and polar, with tryptophan, which is neutral and slightly polar, at codon 2676 of the RYR1 protein (p.Arg2676Trp). This variant is present in population databases (rs193922826, gnomAD 0.003%). This missense change has been observed in individuals with malignant hyperthermia (PMID: 14732627, 19191329, 25960145). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 133217). 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 not expected to disrupt RYR1 protein function with a negative predictive value of 95%. For these reasons, this variant has been classified as Pathogenic. -

Malignant hyperthermia of anesthesia Pathogenic:1

Apr 06, 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 arginine with tryptophan at codon 2676 of the RYR1 protein, p.(Arg2676Trp). The maximum allele frequency for this variant among the six major gnomAD populations is NFE: 0.0000259, a frequency consistent with pathogenicity for MHS. This variant has been reported in eight unrelated individuals who have a personal or family history of a malignant hyperthermia reaction, 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). Two individuals were reported to have a second variant in RYR1 and were not considered for PS4, PS4_Moderate was applied (PMID:30236257, PMID:16163667, PMID:19191329, PMID:25960145, PMID:21157159, Stowell Laboratory personal communication). No functional studies were identified for this variant. This variant does not reside in a hotspot for pathogenic variants that contribute to MHS. This variant segregates with MHS in more than ten individuals, PP1_Strong (PMID:30236257, PMID:25960145, PMID:14732627). A REVEL score of 0.601 supports neither a pathogenic nor a benign status for this variant. This variant has been classified as a Likely Pathogenic. Criteria implemented: PS4_Moderate, PP1_Strong. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.95
BayesDel_addAF	Pathogenic	0.25	D
BayesDel_noAF	Pathogenic	0.18
CADD	Uncertain	23
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.79	.;D
Eigen	Benign	-0.030
Eigen_PC	Benign	-0.18
FATHMM_MKL	Benign	0.29	N
LIST_S2	Pathogenic	0.98	D;D
M_CAP	Uncertain	0.18	D
MetaRNN	Pathogenic	0.92	D;D
MetaSVM	Uncertain	-0.19	T
MutationAssessor	Uncertain	2.0	M;M
PrimateAI	Pathogenic	0.87	D
PROVEAN	Pathogenic	-5.7	D;D
REVEL	Uncertain	0.60
Sift	Uncertain	0.021	D;D
Polyphen		1.0	D;D
Vest4		0.89
MutPred		0.79		Gain of catalytic residue at L2674 (P = 0.0049);Gain of catalytic residue at L2674 (P = 0.0049);
MVP		0.97
MPC		0.65
ClinPred		0.97	D
GERP RS		2.9
Varity_R		0.26
gMVP		0.87

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: rs193922826; hg19: chr19-38994959; COSMIC: COSV100616767;