chr19-38534774-C-T

Variant names:

Variant summary

Our verdict is Uncertain significance. Variant got 4 ACMG points: 4P and 0B. PM5_SupportingPS4_SupportingPP3_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 tryptophan at codon 3772 of the RYR1 protein, p.(Arg3772Trp). The maximum allele frequency for this variant among the six major gnomAD populations is NFE: 0.000027, a frequency consistent with pathogenicity for MHS. 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:19191329). No functional studies were identified for this variant. This variant does not reside in a hotspot for pathogenic variants that contribute to MHS. Another variant has been assessed as likely pathogenic occurs at this codon, p.(Arg3772Gln), PM5_Supporting. A REVEL score >0.85 (0.939) supports a pathogenic status for this variant, PP3_Moderate. This variant has been classified as a Variant of Unknown Significance. Criteria implemented: PS4_Supporting, PM5_Supporting, PP3_Moderate. LINK:https://erepo.genome.network/evrepo/ui/classification/CA056681/MONDO:0007783/012

Frequency

Genomes: 𝑓 0.000020 ( 0 hom., cov: 31)

Exomes 𝑓: 0.0000041 ( 0 hom. )

Consequence

RYR1
NM_000540.3 missense

Scores

Clinical Significance

Uncertain significance reviewed by expert panel P:10U:2

Conservation

PhyloP100: 7.90

Variant links:

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 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 4 ACMG points.

PS4

For more information check the summary or visit ClinGen Evidence Repository.

PM5

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 link	c.11314C>T	p.Arg3772Trp	missense_variant	Exon 79 of 106	ENST00000359596.8	NP_000531.2	P21817-1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
RYR1	ENST00000359596.8 link	c.11314C>T	p.Arg3772Trp	missense_variant	Exon 79 of 106	5	NM_000540.3	ENSP00000352608.2		P21817-1

Frequencies

GnomAD3 genomes

AF:

0.0000197

AC:

AN:

152148

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.0000655

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:

0.0000120

AC:

AN:

250040

Hom.:

AF XY:

0.0000148

AC XY:

AN XY:

135344

show subpopulations

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:

0.0000265

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00000411

AC:

AN:

1461612

Hom.:

Cov.:

AF XY:

0.00000275

AC XY:

AN XY:

727082

show subpopulations

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:

0.00000540

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

AF:

0.0000197

AC:

AN:

152148

Hom.:

Cov.:

AF XY:

0.0000135

AC XY:

AN XY:

74322

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.0000655

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:

0.00000756

ExAC

AF:

0.0000165

AC:

EpiCase

AF:

0.00

EpiControl

AF:

0.0000593

ClinVar

Significance: Uncertain significance

Submissions summary: Pathogenic:10Uncertain:2

Revision: reviewed by expert panel

LINK: link

Submissions by phenotype

not provided

Pathogenic:4

Jul 21, 2015

PreventionGenetics, part of Exact Sciences

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Oct 31, 2016

Clinical Genetics and Genomics, Karolinska University Hospital

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Nov 01, 2019

CeGaT Center for Human Genetics Tuebingen

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Jul 06, 2023

Revvity Omics, Revvity

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Malignant hyperthermia, susceptibility to, 1

Pathogenic:1Uncertain:2

Dec 18, 2023

All of Us Research Program, National Institutes of Health

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This missense variant replaces arginine with tryptophan at codon 3772 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 an individual with personal or family history of a malignant hyperthermia event who tested positive in in vitro contracture testing (PMID: 19191329), as well as in a homozygous individual with a malignant hyperthermia reaction who also carried a variant of uncertain significance in the same gene (PMID: 24091937). This variant has also been observed in individuals with other phenotype(s) (ClinVar variation ID: 478159). This variant has been identified in 3/250040 chromosomes in the general population by the Genome Aggregation Database (gnomAD). Due to insufficient evidence, this variant is classified as a Variant of Uncertain Significance for autosomal dominant malignant hyperthermia. -

Apr 07, 2023

ClinGen Malignant Hyperthermia Susceptibility Variant Curation Expert Panel, ClinGen

Significance: Uncertain significance

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 3772 of the RYR1 protein, p.(Arg3772Trp). The maximum allele frequency for this variant among the six major gnomAD populations is NFE: 0.000027, a frequency consistent with pathogenicity for MHS. 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: 19191329). No functional studies were identified for this variant. This variant does not reside in a hotspot for pathogenic variants that contribute to MHS. Another variant has been assessed as likely pathogenic occurs at this codon, p.(Arg3772Gln), PM5_Supporting. A REVEL score >0.85 (0.939) supports a pathogenic status for this variant, PP3_Moderate. This variant has been classified as a Variant of Unknown Significance. Criteria implemented: PS4_Supporting, PM5_Supporting, PP3_Moderate. -

May 18, 2018

Human Genome Sequencing Center Clinical Lab, Baylor College of Medicine

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.11314C>T (p.Arg3772Trp) variant in the RYR1 gene has been reported in a family with malignant hyperthermia (PMID: 19191329). This variant is also reported in homozygous or compound heterozygous state with other variants in the RYR1 gene in unrelated families with congenital myopathy (PMID: 21062345, 21795085), ophthalmoplegia, facial weakness, and malignant hyperthermia (PMID: 24091937), consistent with an autosomal recessive inheritance pattern for these disorders. Moreover, one variants at the same residue (p.Arg3772Gln) has been described in multiple unrelated individuals with malignant hyperthermia, ptosis, facial weakness, and nonspecific myopathy (PMID: 17483490, 19645060, 21911697, 23553787), suggesting that the p.Arg3772 residue is critical for normal functioning of the RYR1 protein. Multiple lines of prediction algorithms support the deleterious effect of the p.Arg3772Trp variant. In light of the currently available data this variant in the RYR1 gene is classified as likely pathogenic. -

Congenital multicore myopathy with external ophthalmoplegia

Pathogenic:2

Mar 27, 2019

Illumina Laboratory Services, Illumina

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The RYR1 c.11314C>T (p.Arg3772Trp) variant is a missense variant that has been reported in at least two studies and identified in a total of six individuals with minicore myopathy with ophthalmoplegia, including three related individuals in a homozygous state and three in a compound heterozygous state, two of whom were dizygotic twins (Bevilacqua et al. 2011; Shaaban et al. 2013). The p.Arg3772Trp variant is reported at a frequency of 0.000026 in the European (Non-Finnish) population of the Genome Aggregation Database. Another missense variant at the same amino acid position, p.Arg3772Gln, has also been reported in patients in literature (Vladutui et al. 2011). Based on the collective evidence and the application of ACMG codes, the p.Arg3772Trp variant is classified as likely pathogenic for minicore myopathy with ophthalmoplegia. -

Sep 12, 2023

3billion

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The variant is observed at an extremely low frequency in the gnomAD v2.1.1 dataset (total allele frequency: 0.001%). Predicted Consequence/Location: Missense variant In silico tool predictions suggest damaging effect of the variant on gene or gene product [REVEL: 0.94 (>=0.6, sensitivity 0.68 and specificity 0.92)]. Same nucleotide change resulting in same amino acid change has been previously reported as pathogenic/likely pathogenic with strong evidence (ClinVar ID: VCV000478159 /PMID: 19191329). A different missense change at the same codon (p.Arg3772Gln) has been reported as pathogenic/likely pathogenic with strong evidence (ClinVar ID: VCV000133012 /PMID: 17483490). Therefore, this variant is classified as Likely pathogenic according to the recommendation of ACMG/AMP guideline. -

RYR1-related disorder

Pathogenic:1

Nov 29, 2022

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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. ClinVar contains an entry for this variant (Variation ID: 478159). This missense change has been observed in individuals with autosomal recessive RYR1-related conditions (PMID: 21062345, 24091937, 30611313). It has also been observed to segregate with disease in related individuals. This variant has been reported in individual(s) with malignant hyperthermia susceptibility and/or severe statin myopathy (PMID: 19191329, 21795085); however, the role of the variant in this condition is currently unclear. This variant is present in population databases (rs763112609, gnomAD 0.003%). This sequence change replaces arginine, which is basic and polar, with tryptophan, which is neutral and slightly polar, at codon 3772 of the RYR1 protein (p.Arg3772Trp). This variant disrupts the p.Arg3772 amino acid residue in RYR1. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 17483490, 19645060). 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. -

RYR1-related myopathy

Pathogenic:1

Mar 13, 2024

Broad Center for Mendelian Genomics, Broad Institute of MIT and Harvard

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: curation

The homozygous p.Arg3772Trp variant in RYR1 was identified by our study in one individual with external ophthalmoplegia, progressive ptosis, cryptorchidism, and dolichocephaly, via a collaborative study between the Broad Institute's Center for Mendelian Genomics and the Engle lab (https://kirbyneuro.org/EngleLab/). The p.Arg3772Trp variant in RYR1 has been previously reported in 5 unrelated individuals with RYR1-related myopathy (PMID: 21062345, PMID: 24091937, PMID: 19191329, PMID: 33726816), and segregated with disease in 5 affected relatives from 2 families (PMID: 24091937), but has been identified in 0.007% (1/15274) of Latino/Admixed American chromosomes by the Genome Aggregation Database (gnomAD, http://gnomad.broadinstitute.org; dbSNP ID: rs763112609). Although this variant has been seen in the general population in a heterozygous state, its frequency is low enough to be consistent with a recessive carrier frequency. Of these 5 unrelated affected individuals (PMID: 21062345, PMID: 24091937, PMID: 19191329, PMID: 33726816), three were compound heterozygotes who carried variants of uncertain significance in trans (PMID: 21062345, ClinVar ID 847185); PMID: 24091937, NC_000019.10:g.38448402A>G; PMID: 33726816, ClinVar Variation ID: 2230273), which increases the likelihood that the p.Arg3772Trp variant is pathogenic. This variant has also been reported in ClinVar (Variation ID: 478159) and has been interpreted as pathogenic by MGZ Medical Genetics Center and as likely pathogenic by Illumina Laboratory Services for RYR1-related myopathy. One additional likely pathogenic variant, resulting in a different amino acid change at the same position, p.Arg3772Gln, has been reported in association with disease in the literature and in ClinVar, slightly supporting that a change at this position may not be tolerated (PMID: 23553787, PMID: 18253926, PMID: 17483490, PMID: 22473935, PMID: 17483490); Variation ID: 133012). Computational prediction tools and conservation analyses suggest that this variant may impact the protein, though this information is not predictive enough to determine pathogenicity. In summary, although additional studies are required to fully establish its clinical significance, this variant is likely pathogenic for autosomal recessive minicore myopathy with external ophthalmoplegia. ACMG/AMP Criteria applied: PM2_Supporting, PM3, PM5_Supporting, PP1_Strong, PP3 (Richards 2015). -

Central core myopathy

Pathogenic:1

Jul 22, 2021

MGZ Medical Genetics Center

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.94

BayesDel_addAF

Pathogenic

0.43

BayesDel_noAF

Pathogenic

0.45

CADD

Uncertain

DANN

Uncertain

0.99

DEOGEN2

Pathogenic

0.86

.;D;.;.

Eigen

Pathogenic

0.83

Eigen_PC

Pathogenic

0.77

FATHMM_MKL

Pathogenic

0.97

LIST_S2

Pathogenic

1.0

D;D;D;D

M_CAP

Pathogenic

0.73

MetaRNN

Pathogenic

0.98

D;D;D;D

MetaSVM

Pathogenic

0.97

MutationAssessor

Uncertain

2.5

.;M;.;.

PrimateAI

Pathogenic

0.80

PROVEAN

Pathogenic

-6.8

D;D;.;.

REVEL

Pathogenic

0.94

Sift

Pathogenic

0.0

D;D;.;.

Sift4G

Pathogenic

0.0

.;.;D;D

Polyphen

1.0

D;D;.;.

Vest4

0.81

MutPred

0.84

.;Loss of disorder (P = 0.005);.;.;

MVP

1.0

MPC

0.88

ClinPred

0.98

GERP RS

4.8

Varity_R

0.74

gMVP

0.52

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over