rs141646642

Positions:

• chr19-38496278-C-G
• chr19-38496278-C-T

Variant summary

Our verdict is Likely pathogenic. Variant got 5 ACMG points: 5P and 0B. PM1 PP1 PS4_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 histidine with glutamine at codon 2204 of the RYR1 protein, p.(His2204Gln). 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; five 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, MH Investigation Unit (MHIU), UHN, Toronto). This variant segregates with MHS in two meioses PP1 (The UK (Leeds) MH 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 (PMID:21118704). A REVEL score of 0.739 supports neither a pathogenic nor a benign status for this variant. This variant was initially reported to segregate with positive IVCT status in five individuals meeting PP1_Moderate and contributing to a classification of Likely Pathogenic. After review it was determined that an IVCT positive/genotype negative individual in one of the families demonstrating segregation removed that family from consideration (3 meioses) for PP1. The remaining two meisoses would not meet PP1 based on RYR1 specified ACMG rules for variant interpretation. However, the RYR1-MHS VCEP has decided to leave the variant classification at Likely Pathogenic. It it should be noted that this is based on expert opinion and not a strict adherence to the RYR1 specified ACMG rules for variant interpretation. Criteria implemented: PS4_Moderate, PM1, PP1. LINK:https://erepo.genome.network/evrepo/ui/classification/CA024617/MONDO:0018493/012

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000021 (0 hom.)
• Consequence: RYR1 NM_000540.3 missense
• Clinical Significance: Likely pathogenic reviewed by expert panel P:2 U:1 O:1
• Conservation: PhyloP100: -2.45

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 5 ACMG points.

• 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.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
RYR1	NM_000540.3	c.6612C>G	p.His2204Gln	missense_variant	40/106	ENST00000359596.8	NP_000531.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
RYR1	ENST00000359596.8	c.6612C>G	p.His2204Gln	missense_variant	40/106	5	NM_000540.3	ENSP00000352608.2
RYR1	ENST00000355481.8	c.6612C>G	p.His2204Gln	missense_variant	40/105	1		ENSP00000347667.3
RYR1	ENST00000594335.5	n.63C>G		non_coding_transcript_exon_variant	1/49	1		ENSP00000470927.2
RYR1	ENST00000599547.6	n.6612C>G		non_coding_transcript_exon_variant	40/80	2		ENSP00000471601.2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000205 AC: 3 AN: 1461714 Hom.: 0 Cov.: 32 AF XY: 0.00000275 AC XY: 2 AN XY: 727152

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: 0.00000180

Gnomad4 OTH exome AF: 0.0000166

GnomAD4 genome Cov.: 32

ClinVar

Significance: Likely pathogenic

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

Revision: reviewed by expert panel

Submissions by phenotype

not provided Uncertain:1 Other:1

not provided, no classification provided	literature only	Leiden Muscular Dystrophy (RYR1)	-	- -
Uncertain significance, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	Feb 17, 2016	- -

Malignant hyperthermia, susceptibility to, 1 Pathogenic:1

Likely pathogenic, reviewed by expert panel

curation

ClinGen Malignant Hyperthermia Susceptibility Variant Curation Expert Panel, ClinGen

May 22, 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 histidine with glutamine at codon 2204 of the RYR1 protein, p.(His2204Gln). 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; five 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, MH Investigation Unit (MHIU), UHN, Toronto). This variant segregates with MHS in two meioses PP1 (The UK (Leeds) MH 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 (PMID: 21118704). A REVEL score of 0.739 supports neither a pathogenic nor a benign status for this variant. This variant was initially reported to segregate with positive IVCT status in five individuals meeting PP1_Moderate and contributing to a classification of Likely Pathogenic. After review it was determined that an IVCT positive/genotype negative individual in one of the families demonstrating segregation removed that family from consideration (3 meioses) for PP1. The remaining two meisoses would not meet PP1 based on RYR1 specified ACMG rules for variant interpretation. However, the RYR1-MHS VCEP has decided to leave the variant classification at Likely Pathogenic. It it should be noted that this is based on expert opinion and not a strict adherence to the RYR1 specified ACMG rules for variant interpretation. Criteria implemented: PS4_Moderate, PM1, PP1. -

RYR1-related disorder Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Oct 10, 2023

This sequence change replaces histidine, which is basic and polar, with glutamine, which is neutral and polar, at codon 2204 of the RYR1 protein (p.His2204Gln). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with malignant hyperthermia susceptibility and/or autosomal recessive multiminicore disease (PMID: 21674524, 30236257). ClinVar contains an entry for this variant (Variation ID: 133163). 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. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.98
BayesDel_addAF	Pathogenic	0.44	D
BayesDel_noAF	Pathogenic	0.39
CADD	Benign	0.0030
DANN	Benign	0.94
DEOGEN2	Pathogenic	0.96	.;D
Eigen	Benign	-0.57
Eigen_PC	Benign	-0.81
FATHMM_MKL	Benign	0.20	N
LIST_S2	Pathogenic	0.99	D;D
M_CAP	Pathogenic	0.76	D
MetaRNN	Pathogenic	0.97	D;D
MetaSVM	Pathogenic	0.91	D
MutationAssessor	Uncertain	2.7	M;M
PrimateAI	Pathogenic	0.92	D
PROVEAN	Pathogenic	-7.1	D;D
REVEL	Pathogenic	0.74
Sift	Pathogenic	0.0	D;D
Polyphen		1.0	D;D
Vest4		0.92
MutPred		0.80		Loss of catalytic residue at E2205 (P = 0.1845);Loss of catalytic residue at E2205 (P = 0.1845);
MVP		0.97
MPC		0.35
ClinPred		0.90	D
GERP RS		-6.9
Varity_R		0.82
gMVP		0.93

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs141646642; hg19: chr19-38986918;