chr19-38565034-G-C

Variant names:

• chr19-38565034-G-C
• rs193922852
• NM_000540.3:c.12700G>C

Variant summary

Our verdict is Likely pathogenic. The variant received 8 ACMG points: 8P and 0B. PS4_Moderate PP3_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 valine with leucine at codon 4324 of the RYR1 protein, p.(Val4234Leu); c.12700G>C. This variant was not present in a large population database (gnomAD) at the time this variant was interpreted. This variant has been reported in six 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_Moderate (PMID:30236257, 12208234, 21965348, 22696611, 24053352, 28290972). This variant segregates with MHS in nine meiosis, PP1_Strong (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. A REVEL score >0.85 (0.89) supports a pathogenic status for this variant, PP3_Moderate. This variant has been classified as Likely Pathogenic. Criteria implemented: PS4_Moderate, PP1_Strong, PP3_Moderate. LINK:https://erepo.genome.network/evrepo/ui/classification/CA024001/MONDO:0018493/012

• Frequency: Genomes: not found (cov: 32)
• Consequence: RYR1 NM_000540.3 missense
• Clinical Significance: Likely pathogenic reviewed by expert panel P:6 O:1
• Conservation: PhyloP100: 8.00
• Publications: 7 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: Likely_pathogenic. The variant received 8 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.
• PP3: For more information check the summary or visit ClinGen Evidence Repository.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_000540.3. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	RYR1	NM_000540.3	MANE Select	c.12700G>C	p.Val4234Leu	missense	Exon 91 of 106	NP_000531.2
	RYR1	NM_001042723.2		c.12685G>C	p.Val4229Leu	missense	Exon 90 of 105	NP_001036188.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	RYR1	ENST00000359596.8	TSL:5 MANE Select	c.12700G>C	p.Val4234Leu	missense	Exon 91 of 106	ENSP00000352608.2
	RYR1	ENST00000355481.8	TSL:1	c.12685G>C	p.Val4229Leu	missense	Exon 90 of 105	ENSP00000347667.3
	RYR1	ENST00000594335.6	TSL:1	n.*3410G>C		non_coding_transcript_exon	Exon 88 of 103	ENSP00000470927.2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

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

Dec 18, 2023

All of Us Research Program, National Institutes of Health

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This missense variant replaces valine with leucine at codon 4234 of the RYR1 protein. Computational prediction suggests that this variant may have deleterious impact on protein structure and function (internally defined REVEL score threshold >= 0.7, PMID: 27666373). To our knowledge, functional studies have not been reported for this variant. This variant has been reported in at least 10 individuals affected with malignant hyperthermia susceptibility (PMID: 12208234, 16835904, 19191333, 20681998, 21965348, 22696611, 24013571, 24053352, 28290972, 30236257, 30916033). This variant has been reported to segregate with malignant hyperthermia susceptibility in nine meiosis in family studies (ClinVar: SCV001653555.1). This variant has not been identified in the general population by the Genome Aggregation Database (gnomAD). Based on the available evidence, this variant is classified as Likely Pathogenic.

Mar 30, 2023

Molecular Genetics, Royal Melbourne Hospital

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change is predicted to replace valine with leucine at codon 4234 in exon 91 of the RYR1 protein, p.(Val4234Leu). The valine residue is highly conserved (100 vertebrates, UCSC), and is located in the RYR1 channel and acitvation core. There is a small physicochemical difference between valine and leucine. The variant is absent in a large population cohort (gnomAD v2.1 and v3.1). The variant has been identified in at least four individuals with malignant hyperthermia susceptibility (MHS) or a family history of MHS confirmed by a positive in vitro contracture test, and segregates with MHS (PMID: 20681998, 24053352, 28290972; ClinVar: SCV001653555.1, Royal Melbourne Hospital). Multiple lines of computational evidence have conflicting predictions for the missense substitution (3/5 algorithms predict deleterious). The same amino acid change (p.Val4234Leu), resulting from a different nucleotide change c.12700G>T, has been reported in individuals with MHS (PMID: 24013571, 30236257; ClinVar ID: 1071064). Based on the classification scheme RMH Modified ACMG Guidelines v1.5.1, this variant is classified as LIKELY PATHOGENIC. Following criteria are met: PP1_Strong, PS4_Moderate.

May 06, 2024

Color Diagnostics, LLC DBA Color Health

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This missense variant replaces valine with leucine at codon 4234 of the RYR1 protein. Computational prediction suggests that this variant may have deleterious impact on protein structure and function. To our knowledge, functional studies have not been reported for this variant. This variant has been reported in at least 10 individuals affected with malignant hyperthermia susceptibility (PMID: 12208234, 16835904, 19191333, 20681998, 21965348, 22696611, 24013571, 24053352, 28290972, 30236257, 30916033, 37873543). This variant has been reported to segregate with malignant hyperthermia susceptibility in nine meiosis in family studies (ClinVar: SCV001653555.1). This variant has not been identified in the general population by the Genome Aggregation Database (gnomAD). Based on the available evidence, this variant is classified as Likely Pathogenic.

Malignant hyperthermia of anesthesia Pathogenic:2

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 valine with leucine at codon 4324 of the RYR1 protein, p.(Val4234Leu); c.12700G>C. This variant was not present in a large population database (gnomAD) at the time this variant was interpreted. This variant has been reported in six 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_Moderate (PMID: 30236257, 12208234, 21965348, 22696611, 24053352, 28290972). This variant segregates with MHS in nine meiosis, PP1_Strong (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. A REVEL score >0.85 (0.89) supports a pathogenic status for this variant, PP3_Moderate. This variant has been classified as Likely Pathogenic. Criteria implemented: PS4_Moderate, PP1_Strong, PP3_Moderate.

Jul 25, 2025

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Variant summary: RYR1 c.12700G>C (p.Val4234Leu) results in a conservative amino acid change in the encoded protein sequence. Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change. The frequency data for this variant in gnomAD is considered unreliable, as metrics indicate poor data quality at this position. c.12700G>C has been observed in multiple individuals affected with Malignant Hyperthermia Susceptibility (e.g., Galli_2002, Miller_2018). These data indicate that the variant is very likely to be associated with disease. The following publications have been ascertained in the context of this evaluation (PMID: 12208234, 30236257). ClinVar contains an entry for this variant (Variation ID: 133040). Based on the evidence outlined above, the variant was classified as pathogenic.

RYR1-related disorder Pathogenic:1

Oct 27, 2023

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change replaces valine, which is neutral and non-polar, with leucine, which is neutral and non-polar, at codon 4234 of the RYR1 protein (p.Val4234Leu). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with malignant hyperthermia susceptibility (PMID: 12208234, 24013571, 30236257). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 133040). 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) has been performed at Invitae 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. For these reasons, this variant has been classified as Pathogenic.

not provided Other:1

RYR1 database

Significance: not provided

Review Status: no classification provided

Collection Method: literature only

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.89
BayesDel_addAF	Pathogenic	0.38	D
BayesDel_noAF	Pathogenic	0.31
CADD	Uncertain	23
DANN	Benign	0.93
DEOGEN2	Uncertain	0.73	D
Eigen	Uncertain	0.41
Eigen_PC	Uncertain	0.37
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Pathogenic	0.99	D
M_CAP	Pathogenic	0.64	D
MetaRNN	Pathogenic	0.89	D
MetaSVM	Pathogenic	0.93	D
MutationAssessor	Uncertain	2.5	M
PhyloP100		8.0
PrimateAI	Pathogenic	0.82	D
PROVEAN	Benign	-2.3	N
REVEL	Pathogenic	0.89
Sift	Uncertain	0.0030	D
Polyphen		0.71	P
Vest4		0.61
MutPred		0.84		Loss of ubiquitination at K4229 (P = 0.1852)
MVP		0.99
MPC		0.56
ClinPred		0.97	D
GERP RS		3.1
PromoterAI		0.0089	Neutral
Varity_R		0.45
gMVP		0.97
Mutation Taster		=1/99	disease causing

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: rs193922852; hg19: chr19-39055674;