rs193922766

Variant names:

• chr19-38451843-G-A
• rs193922766
• NM_000540.3:c.1202G>A

Your query was ambiguous. Multiple possible variants found:

• chr19-38451843-G-A
• chr19-38451843-G-T

Variant summary

Our verdict is Pathogenic. The variant received 11 ACMG points: 11P and 0B. PS4 PS3_Moderate PM1 PP1 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 arginine with histidine at codon 401 of the RYR1 protein, p.(Arg401His). The maximum allele frequency for this variant in the Finish population in gnomAD was 0.000046 with one alternate allele. This variant was not identified in any of the six continental populations in gnomAD. This is consistent with pathogenicity. This variant has been reported in eight unrelated individuals who have a personal or family history of a malignant hyperthermia reaction, eight 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 (PMID:12059893, PMID:16163667, PMID:30236257, PMID:23460944, PMID:24433488). This variant segregates with MHS in three individuals, PP1_Supporting ( PMID:12059893). Functional studies in HEK293 cells show an increased sensitivity to RYR1 agonists PS3_Moderate (PMID:26115329, PMID:31841587). This variant resides in a region of RYR1 considered to be a hotspot for pathogenic variants that contribute to MHS, PM1 (PMID:21118704). This variant segregates with MHS in three individuals, PP1_Supporting (PMID:12059893). A REVEL score >0.85 (0.903) supports a pathogenic status for this variant, PP3_Moderate. This variant has been classified as Pathogenic. Criteria implemented: PS3_Moderate, PS4, PM1, PP1_Supporting, PP3_Moderate.  LINK:https://erepo.genome.network/evrepo/ui/classification/CA023959/MONDO:0007783/012

• Frequency:
  • Genomes: not found (cov: 31)
  • Exomes 𝑓: 0.0000014 (0 hom.)
• Consequence: RYR1 NM_000540.3 missense
• Clinical Significance: Pathogenic reviewed by expert panel P:6 O:1
• Conservation: PhyloP100: 9.86
• Publications: 9 publications found

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 Gene-Disease associations (from GenCC):

• malignant hyperthermia, susceptibility to, 1

  Inheritance: AD Classification: DEFINITIVE, STRONG Submitted by: Labcorp Genetics (formerly Invitae), ClinGen, Genomics England PanelApp, Ambry Genetics
• congenital multicore myopathy with external ophthalmoplegia

  Inheritance: AR Classification: DEFINITIVE, STRONG Submitted by: G2P, Genomics England PanelApp
• RYR1-related myopathy

  Inheritance: AR, AD Classification: DEFINITIVE Submitted by: ClinGen
• central core myopathy

  Inheritance: AD, AR Classification: STRONG, SUPPORTIVE Submitted by: Labcorp Genetics (formerly Invitae), Orphanet, Genomics England PanelApp
• King-Denborough syndrome

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• malignant hyperthermia of anesthesia

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• autosomal recessive centronuclear myopathy

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet
• benign Samaritan congenital myopathy

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet
• congenital myopathy with myasthenic-like onset

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet
• lethal multiple pterygium syndrome

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Pathogenic. The variant received 11 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.
• 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.1202G>A	p.Arg401His	missense_variant	Exon 12 of 106	ENST00000359596.8	NP_000531.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
RYR1	ENST00000359596.8	c.1202G>A	p.Arg401His	missense_variant	Exon 12 of 106	5	NM_000540.3	ENSP00000352608.2

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD2 exomes AF: 0.00000398 AC: 1 AN: 251410 AF XY: 0.00

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 FIN exome AF: 0.0000462

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000137 AC: 2 AN: 1461868 Hom.: 0 Cov.: 31 AF XY: 0.00 AC XY: 0 AN XY: 727240

African (AFR) AF: 0.0000299 AC: 1 AN: 33480

American (AMR) AF: 0.00 AC: 0 AN: 44720

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26132

East Asian (EAS) AF: 0.00 AC: 0 AN: 39700

South Asian (SAS) AF: 0.00 AC: 0 AN: 86258

European-Finnish (FIN) AF: 0.0000187 AC: 1 AN: 53418

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5768

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1111996

Other (OTH) AF: 0.00 AC: 0 AN: 60396

GnomAD4 genome Cov.: 31

Alfa AF: 0.00 Hom.: 0

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:6 Other:1

Revision: reviewed by expert panel

Submissions by phenotype

Malignant hyperthermia, susceptibility to, 1 Pathogenic:2

Apr 10, 2024

All of Us Research Program, National Institutes of Health

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.1202G>A (p.Arg401His) variant of the RYR1 gene is a missense variant that replaces Arginine with Histidine at codon 401 of the RYR1 protein. This variant has been reported in seven unrelated individuals who have a personal or family history of a malignant hyperthermia reaction, and all these individuals had a positive in vitro contracture test (IVCT) or caffeine halothane contracture test (CHCT) result (PMID:12059893, 16163667, 30236257, 23460944, 24433488). The p.Arg401His variant has been shown to segregate with MHS in three individuals (PMID:12059893). This variant resides in a region of RYR1 considered to be a hotspot for pathogenic variants that contribute to malignant hyperthermia. Functional studies in HEK293 cells shows an increased sensitivity to RYR1 agonists (PMID: 26115329, 31841587). Computational prediction suggests that this variant may have deleterious impact on protein structure and function (REVEL 0.903, PMID: 27666373). Alteration affecting the same amino acid, c.1201C>T (p.Arg401Cys) and c.1202G>T (p.Arg401Leu), were classified as pathogenic and like pathogenic by the expert panel in ClinVar, respectively (ID:133029 and 983140). Based on the supporting evidence, this c.1202G>A (p.Arg401His) variant of RYR1 gene is classified as pathogenic. -

Mar 18, 2021

ClinGen Malignant Hyperthermia Susceptibility Variant Curation Expert Panel, ClinGen

Significance: 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 histidine at codon 401 of the RYR1 protein, p.(Arg401His). The maximum allele frequency for this variant in the Finish population in gnomAD was 0.000046 with one alternate allele. This variant was not identified in any of the six continental populations in gnomAD. This is consistent with pathogenicity. This variant has been reported in eight unrelated individuals who have a personal or family history of a malignant hyperthermia reaction, eight 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 (PMID:12059893, PMID:16163667, PMID:30236257, PMID:23460944, PMID:24433488). This variant segregates with MHS in three individuals, PP1_Supporting ( PMID:12059893). Functional studies in HEK293 cells show an increased sensitivity to RYR1 agonists PS3_Moderate (PMID:26115329, PMID:31841587). This variant resides in a region of RYR1 considered to be a hotspot for pathogenic variants that contribute to MHS, PM1 (PMID: 21118704). This variant segregates with MHS in three individuals, PP1_Supporting (PMID:12059893). A REVEL score >0.85 (0.903) supports a pathogenic status for this variant, PP3_Moderate. This variant has been classified as Pathogenic. Criteria implemented: PS3_Moderate, PS4, PM1, PP1_Supporting, PP3_Moderate. -

not provided Pathogenic:1 Other:1

-

RYR1 database

Significance: not provided

Review Status: no classification provided

Collection Method: literature only

- -

Jun 01, 2024

CeGaT Center for Human Genetics Tuebingen

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

RYR1: PP1:Strong, PM1, PM5, PS4:Moderate, PS3:Supporting -

RYR1-related disorder Pathogenic:1

Sep 09, 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 histidine, which is basic and polar, at codon 401 of the RYR1 protein (p.Arg401His). This variant is present in population databases (rs193922766, gnomAD 0.004%). This missense change has been observed in individuals with autosomal dominant malignant hyperthermia as well as autosomal recessive RYR1-related myopathy (PMID: 12059893, 24433488; internal data). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 133030). Invitae Evidence Modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) has been performed for this missense variant. However, the output from this modeling did not meet the statistical confidence thresholds required to predict the impact of this variant on RYR1 protein function. This variant disrupts the p.Arg401 amino acid residue in RYR1. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 12066726, 16084090, 24433488, 25735680). 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. -

Malignant hyperthermia of anesthesia Pathogenic:1

Jun 11, 2020

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The p.Arg401His variant in RYR1 has been reported in 3 probands with malignant hyperthermia and segregated in 3 affected family members (Klingler 2014, Rueffert 2002). This variant was identified in 1/21644 of Finnish chromosomes by gnomAD (http://gnomad.broadinstitute.org). Several additional variants have been reported at amino acid position 401, including p.Arg401Cys which is classified as pathogenic / likely pathogenic in ClinVar (Variation ID 133029). In summary, although additional studies are required to fully establish its clinical significance, this variant meets criteria to be classified as likely pathogenic for autosomal dominant malignant hyperthermia. ACMG/AMP Criteria applied: PM2, PM5, PS4_Moderate, PP1. -

RYR1-related myopathy Pathogenic:1

Mar 01, 2024

Muscle and Diseases Team, Institut de Génétique et Biologie Moléculaire et Cellulaire

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: research

PM1+PM2+PM5+PP2+PP3 -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.42
BayesDel_addAF	Pathogenic	0.51	D
BayesDel_noAF	Pathogenic	0.49
CADD	Pathogenic	26
DANN	Uncertain	0.98
DEOGEN2	Uncertain	0.73	.;D
Eigen	Uncertain	0.68
Eigen_PC	Uncertain	0.62
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Pathogenic	0.99	D;D
M_CAP	Pathogenic	0.36	D
MetaRNN	Pathogenic	0.97	D;D
MetaSVM	Pathogenic	1.0	D
MutationAssessor	Pathogenic	2.9	M;M
PhyloP100		9.9
PrimateAI	Uncertain	0.70	T
PROVEAN	Uncertain	-3.8	D;D
REVEL	Pathogenic	0.90
Sift	Uncertain	0.0010	D;D
Polyphen		0.97	D;D
Vest4		0.81
MutPred		0.87		Loss of MoRF binding (P = 0.0741);Loss of MoRF binding (P = 0.0741);
MVP		1.0
MPC		1.0
ClinPred		0.99	D
GERP RS		4.2
Varity_R		0.46
gMVP		0.72
Mutation Taster		=1/99	disease causing (ClinVar)

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

Other links and lift over

dbSNP: rs193922766; hg19: chr19-38942483; COSMIC: COSV62103608;