19-38580440-G-A

Position:

• chr19-38580440-G-A

Variant summary

Our verdict is Pathogenic. Variant got 14 ACMG points: 14P and 0B. PS2 PS4 PS3_Supporting PM5 PM2_Supporting PP1 PP3

This summary comes from the ClinGen Evidence Repository: The NM_000540.3:c.14582G>A variant in RYR1 is a missense variant predicted to cause substitution of arginine by histidine at amino acid 4861 (p.Arg4861His). The highest population minor allele frequency in gnomAD v4.1 is 0.0000008475 (1/1180004 alleles) in the European (non-Finnish) population, which is lower than the ClinGen Congenital Myopathies VCEP threshold (absent with 1 allele allowed) for PM2_Supporting, meeting this criterion (PM2_Supporting). The REVEL computational prediction analysis tool gives a score of 0.912, which is above the threshold necessary to apply PP3. Four different missense variants, c.14581C>A (p.Arg4861Ser), c.14581C>G (p.Arg4861Gly), c.14581C>T (p.Arg4861Cys), c.14582G>C (p.Arg4861Pro) (ClinVar IDs: 2027376, 943431, 65986, 1066439), in the same codon have been classified as pathogenic/likely pathogenic for RYR1-related myopathy (PM5). This variant has been reported in at least five probands with RYR1-related myopathy which meets the criteria for PS4, two of which were confirmed to be de novo occurrences meeting PS2 (PMIDs:11709545, 35428369, 35081925). The variant has also been reported to segregate in one affected sibling from a family (PP1, PMID:11709545). Calcium homeostasis analysis of immortalized B-lymphocytes from patients showed significantly smaller thapsigargin-sensitive intracellular calcium stores, compared to lymphoblasts from control individuals, indicating that this variant may impact protein function (PS3_Supporting, PMID:11741831). In summary, the variant meets the criteria to be classified as pathogenic for autosomal dominant RYR1-related myopathy. ACMG/AMP criteria met, as specified by the ClinGen Congenital Myopathies VCEP: PS4, PS2, PS3_Supporting, PM5, PM2_Supporting, PP1, PP3 (ClinGen Congenital Myopathies VCEP specifications version 1; 8/7/2024). LINK:https://erepo.genome.network/evrepo/ui/classification/CA024187/MONDO:0100150/150

• Frequency:
  • Genomes: not found (cov: 31)
  • Exomes 𝑓: 6.8e-7 (0 hom.)
• Consequence: RYR1 NM_000540.3 missense
• Clinical Significance: Uncertain significance; drug response reviewed by expert panel P:11 U:1 O:8
• Conservation: PhyloP100: 9.95

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 Pathogenic. Variant got 14 ACMG points.

• PS2: For more information check the summary or visit ClinGen Evidence Repository.
• PS3: For more information check the summary or visit ClinGen Evidence Repository.
• PS4: For more information check the summary or visit ClinGen Evidence Repository.
• PM2: 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/exons	MANE	Protein	UniProt
RYR1	NM_000540.3	c.14582G>A	p.Arg4861His	missense_variant	101/106	ENST00000359596.8	NP_000531.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
RYR1	ENST00000359596.8	c.14582G>A	p.Arg4861His	missense_variant	101/106	5	NM_000540.3	ENSP00000352608	A2

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome AF: 6.84e-7 AC: 1 AN: 1461872 Hom.: 0 Cov.: 34 AF XY: 0.00000138 AC XY: 1 AN XY: 727236

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: 8.99e-7

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 31

ClinVar

Significance: Uncertain significance; drug response

Submissions summary: Pathogenic:11 Uncertain:1 Other:8

Revision: reviewed by expert panel

Submissions by phenotype

not provided Pathogenic:6 Other:1

Pathogenic, criteria provided, single submitter	clinical testing	Laboratory of Molecular Genetics (Pr. Bezieau's lab), CHU de Nantes	Jan 22, 2018	- -
not provided, no classification provided	literature only	Leiden Muscular Dystrophy (RYR1)	-	- -
Pathogenic, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	Nov 15, 2017	- -
Pathogenic, criteria provided, single submitter	clinical testing	Genetic Services Laboratory, University of Chicago	Mar 10, 2017	- -
Pathogenic, criteria provided, single submitter	clinical testing	Revvity Omics, Revvity	Oct 17, 2019	- -
Pathogenic, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Jan 01, 2021	- -
Pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Jan 03, 2024	Reported multiple times in association with autosomal dominant central core disease (PMID: 11709545, 12565913, 17226826, RYR1 LOVD); Published functional studies demonstrate that R4861H significantly alters intracellular calcium homeostasis (PMID: 11741831); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Not observed at significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 27708273, 33458582, 11709545, 17483490, 17538032, 16621918, 17226826, 25521991, 11741831, 29629541, 27363342, 32403337, 33333461, 33726816, 31785789, 33087929, 35693006, 29576327, 35428369, 35081925, 12565913, 23394784, 20681998) -

Central core myopathy Pathogenic:2

Pathogenic, criteria provided, single submitter	clinical testing	Center for Genomic Medicine, King Faisal Specialist Hospital and Research Center	Apr 04, 2024	- -
Pathogenic, no assertion criteria provided	literature only	OMIM	Jan 08, 2008	- -

Malignant hyperthermia, susceptibility to, 1 Pathogenic:1 Uncertain:1

Uncertain significance, reviewed by expert panel	curation	ClinGen Malignant Hyperthermia Susceptibility Variant Curation Expert Panel, ClinGen	May 20, 2023	This variant has strong evidence towards pathogenicity as a myopathy variant and 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 4861 of the RYR1 protein, p.(Arg4861His). This variant was not present in a large population database (gnomAD) at the time this variant was interpreted. This variant has been reported in an individual with a personal or family history of an MH episode and 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_Supporting (PMID: 23558838). This variant has also been identified in two individuals with negative IVCT/CHCT results, BS2 (The UK (Leeds) MH Unit). Functional studies in HEK293 cells show an increased sensitivity to RYR1 agonists, PS3_Moderate (PMID: 30236257). Additionally, a functional study in patient myotubes showed increased resting calcium and increased ECCE compared to controls (PMID: 21088110). This variant resides in a region of RYR1 considered to be a hotspot for pathogenic variants that contribute to MHS, PM1_Sup (PMID: 21118704). A REVEL score >0.85 (0.912) supports a pathogenic status for this variant, PP3_Moderate. This variant has been classified as a Variant of Unknown Significance in relation to MHS. Criteria implemented: PS3_Moderate, PS4_Supporting, PM1_Supporting, PP3_Moderate, BS2. -
Pathogenic, criteria provided, single submitter	research	HudsonAlpha Institute for Biotechnology, HudsonAlpha Institute for Biotechnology	Sep 11, 2018	- -

RYR1-related disorder Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Nov 04, 2023

This sequence change replaces arginine, which is basic and polar, with histidine, which is basic and polar, at codon 4861 of the RYR1 protein (p.Arg4861His). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individuals with autosomal dominant central core disease (PMID: 11709545, 12565913, 14670767, 23394784, 25521991). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 12982). 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 with a positive predictive value of 95%. Experimental studies have shown that this missense change affects RYR1 function (PMID: 11741831). For these reasons, this variant has been classified as Pathogenic. -

Malignant hyperthermia of anesthesia Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Jun 11, 2020

The p.Arg4861His variant in RYR1 has been reported in many heterozygous individuals with central core disease, segregated in many affected heterozygous relatives, and has been reported as a de novo variant in several cases (Brandom 2013 PMID 23558838, Broman 2007 PMID 17081152, Broman 2015 PMID 25989378, Davis 2003 PMID 12565913, Jeong 2018 PMID 29629541, Kossugue 2007 PMID 17226826, Lee 2014 PMID 25521991, Maggi 2013 PMID 23394784, Marks 2018 PMID 29576327, Monnier 2001 PMID 11709545, Park 2017 PMID 27363342, Reddy 2017 PMID 27708273, Sato 2008 PMID 17538032, Shepherd 2004 PMID 14985404, Tilgen 2001 PMID 11741831, Treves 2005 PMID 16084090, Wu 2006 PMID 16621918, Zhou 2007 PMID 17483490). It has also been reported in at least one individual with malignant hyperthermia susceptibility (Brandom 2013 PMID 23558838) and in ClinVar by the PharmGKB expert panel with evidence level 1A for susceptibility to malignant hyperthermia, the annotation for a variant-drug combination in a CPIC or medical society-endorsed PGx guideline (Variation ID 12982). It is absent from large population studies. Computational prediction tools and conservation analysis suggest that this variant may impact the protein. Furthermore, in vitro functional studies provide some evidence that this variant impacts protein function (Tilgen 2001 PMID 11741831). In summary, this variant meets criteria to be classified as pathogenic for autosomal dominant central core disease but has also been reported in MH susceptibility. ACMG/AMP criteria applied: PS4, PM6_Strong, PP1_Strong, PM2, PP3, PS3_Supporting. -

methoxyflurane response - Toxicity Other:1

drug response, reviewed by expert panel

curation

PharmGKB

Mar 24, 2021

PharmGKB Level of Evidence 1A: Level 1A clinical annotations describe variant-drug combinations that have variant-specific prescribing guidance available in a current clinical guideline annotation or an FDA-approved drug label annotation. Annotations of drug labels or clinical guidelines must give prescribing guidance for specific variants (e.g. CYP2C9*3, HLA-B*57:01) or provide mapping from defined allele functions to diplotypes and phenotypes to be used as supporting evidence for a level 1A clinical annotation. Level 1A clinical annotations must also be supported by at least one publication in addition to a clinical guideline or drug label with variant-specific prescribing guidance. Drug-variant association: Toxicity

sevoflurane response - Toxicity Other:1

drug response, reviewed by expert panel

curation

PharmGKB

Mar 24, 2021

PharmGKB Level of Evidence 1A: Level 1A clinical annotations describe variant-drug combinations that have variant-specific prescribing guidance available in a current clinical guideline annotation or an FDA-approved drug label annotation. Annotations of drug labels or clinical guidelines must give prescribing guidance for specific variants (e.g. CYP2C9*3, HLA-B*57:01) or provide mapping from defined allele functions to diplotypes and phenotypes to be used as supporting evidence for a level 1A clinical annotation. Level 1A clinical annotations must also be supported by at least one publication in addition to a clinical guideline or drug label with variant-specific prescribing guidance. Drug-variant association: Toxicity

isoflurane response - Toxicity Other:1

drug response, reviewed by expert panel

curation

PharmGKB

Mar 24, 2021

PharmGKB Level of Evidence 1A: Level 1A clinical annotations describe variant-drug combinations that have variant-specific prescribing guidance available in a current clinical guideline annotation or an FDA-approved drug label annotation. Annotations of drug labels or clinical guidelines must give prescribing guidance for specific variants (e.g. CYP2C9*3, HLA-B*57:01) or provide mapping from defined allele functions to diplotypes and phenotypes to be used as supporting evidence for a level 1A clinical annotation. Level 1A clinical annotations must also be supported by at least one publication in addition to a clinical guideline or drug label with variant-specific prescribing guidance. Drug-variant association: Toxicity

enflurane response - Toxicity Other:1

drug response, reviewed by expert panel

curation

PharmGKB

Mar 24, 2021

PharmGKB Level of Evidence 1A: Level 1A clinical annotations describe variant-drug combinations that have variant-specific prescribing guidance available in a current clinical guideline annotation or an FDA-approved drug label annotation. Annotations of drug labels or clinical guidelines must give prescribing guidance for specific variants (e.g. CYP2C9*3, HLA-B*57:01) or provide mapping from defined allele functions to diplotypes and phenotypes to be used as supporting evidence for a level 1A clinical annotation. Level 1A clinical annotations must also be supported by at least one publication in addition to a clinical guideline or drug label with variant-specific prescribing guidance. Drug-variant association: Toxicity

halothane response - Toxicity Other:1

drug response, reviewed by expert panel

curation

PharmGKB

Mar 24, 2021

PharmGKB Level of Evidence 1A: Level 1A clinical annotations describe variant-drug combinations that have variant-specific prescribing guidance available in a current clinical guideline annotation or an FDA-approved drug label annotation. Annotations of drug labels or clinical guidelines must give prescribing guidance for specific variants (e.g. CYP2C9*3, HLA-B*57:01) or provide mapping from defined allele functions to diplotypes and phenotypes to be used as supporting evidence for a level 1A clinical annotation. Level 1A clinical annotations must also be supported by at least one publication in addition to a clinical guideline or drug label with variant-specific prescribing guidance. Drug-variant association: Toxicity

desflurane response - Toxicity Other:1

drug response, reviewed by expert panel

curation

PharmGKB

Mar 24, 2021

PharmGKB Level of Evidence 1A: Level 1A clinical annotations describe variant-drug combinations that have variant-specific prescribing guidance available in a current clinical guideline annotation or an FDA-approved drug label annotation. Annotations of drug labels or clinical guidelines must give prescribing guidance for specific variants (e.g. CYP2C9*3, HLA-B*57:01) or provide mapping from defined allele functions to diplotypes and phenotypes to be used as supporting evidence for a level 1A clinical annotation. Level 1A clinical annotations must also be supported by at least one publication in addition to a clinical guideline or drug label with variant-specific prescribing guidance. Drug-variant association: Toxicity

succinylcholine response - Toxicity Other:1

drug response, reviewed by expert panel

curation

PharmGKB

Mar 24, 2021

PharmGKB Level of Evidence 1A: Level 1A clinical annotations describe variant-drug combinations that have variant-specific prescribing guidance available in a current clinical guideline annotation or an FDA-approved drug label annotation. Annotations of drug labels or clinical guidelines must give prescribing guidance for specific variants (e.g. CYP2C9*3, HLA-B*57:01) or provide mapping from defined allele functions to diplotypes and phenotypes to be used as supporting evidence for a level 1A clinical annotation. Level 1A clinical annotations must also be supported by at least one publication in addition to a clinical guideline or drug label with variant-specific prescribing guidance. Drug-variant association: Toxicity

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.93
BayesDel_addAF	Pathogenic	0.49	D
BayesDel_noAF	Pathogenic	0.47
CADD	Pathogenic	26
DANN	Uncertain	0.99
DEOGEN2	Pathogenic	0.98	.;D
Eigen	Pathogenic	0.94
Eigen_PC	Pathogenic	0.86
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Pathogenic	1.0	D;D
M_CAP	Pathogenic	0.77	D
MetaRNN	Pathogenic	0.97	D;D
MetaSVM	Pathogenic	1.0	D
MutationAssessor	Pathogenic	3.1	.;M
MutationTaster	Benign	1.0	A;A;A
PrimateAI	Pathogenic	0.89	D
PROVEAN	Uncertain	-4.3	D;D
REVEL	Pathogenic	0.91
Sift	Pathogenic	0.0	D;D
Polyphen		1.0	D;D
Vest4		0.80
MutPred		0.87		.;Loss of stability (P = 0.0924);
MVP		1.0
MPC		0.71
ClinPred		1.0	D
GERP RS		4.7
Varity_R		0.87
gMVP		0.97

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: rs63749869; hg19: chr19-39071080;