19-38519399-T-G

Variant names:

Variant summary

Our verdict is Pathogenic. Variant got 4 ACMG points: 4P and 0B. PM3PP3PP1

This summary comes from the ClinGen Evidence Repository: The NM_000540.3:c.10204T>G (p.Cys3402Gly) variant in RYR1 is a missense variant predicted to cause a substitution of cysteine by glycine at amino acid 3402. The computational predictor REVEL gives a score of 0.851, which is above the threshold for predicting a damaging effect on RYR1 variants (PP3). The highest population minor allele frequency in gnomAD v4.1.0 is 0.00006 (7/117872 alleles) in European (non-Finnish) population, which is higher than the ClinGen Congenital Myopathies VCEP threshold (≤0.00000697) for PM2_Supporting and lower than ClinGen Congenital Myopathies VCEP threshold (≥0.000697) for BS1, therefore no population criteria can be applied. The variant has been reported in trans with a second pathogenic RYR1 variant or a rare variant of uncertain significance in RYR1 in 10 probands with clinical features of congenital myopathy (PMID:20583297; Synnovis internal data SCV001468505.1; Invitae internal data SCV000659742.9) (PM3_Very Strong). The variant along with another pathogenic variant in trans was identified in two siblings with congenital myopathy suggesting cosegregation (Invitae internal data) (PP1). In summary, this variant meets the criteria to be classified as pathogenic for autosomal recessive RYR1-related myopathy based on the ACMG/AMP criteria applied as specified by the ClinGen Congenital Myopathy VCEP: PM3_Very Strong, PP1, PP3 (ClinGen Congenital Myopathies VCEP Specifications 2.0.0; 2/10/2025). LINK:https://erepo.genome.network/evrepo/ui/classification/CA023822/MONDO:0100150/179

Frequency

Genomes: 𝑓 0.000046 ( 0 hom., cov: 32)

Exomes 𝑓: 0.000072 ( 0 hom. )

Consequence

RYR1
NM_000540.3 missense

Scores

Clinical Significance

Pathogenic reviewed by expert panel P:9U:3O:1

Conservation

PhyloP100: 1.35

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 Pathogenic. Variant got 4 ACMG points.

PM3

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 link	c.10204T>G	p.Cys3402Gly	missense_variant	Exon 67 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.10204T>G	p.Cys3402Gly	missense_variant	Exon 67 of 106	5	NM_000540.3	ENSP00000352608.2		P21817-1

Frequencies

GnomAD3 genomes

AF:

0.0000460

AC:

AN:

152192

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

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:

0.000103

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000217

AC:

AN:

230648

Hom.:

AF XY:

0.0000321

AC XY:

AN XY:

124666

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:

0.0000488

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000716

AC:

104

AN:

1451882

Hom.:

Cov.:

AF XY:

0.0000693

AC XY:

AN XY:

721588

show subpopulations

Gnomad4 AFR exome

AF:

0.0000302

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:

0.0000866

Gnomad4 OTH exome

AF:

0.000117

GnomAD4 genome

AF:

0.0000460

AC:

AN:

152192

Hom.:

Cov.:

AF XY:

0.0000269

AC XY:

AN XY:

74364

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.000103

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.000108

Hom.:

Bravo

AF:

0.0000453

ExAC

AF:

0.0000165

AC:

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:9Uncertain:3Other:1

Revision: reviewed by expert panel

LINK: link

Submissions by phenotype

not provided

Pathogenic:4Uncertain:1

Sep 14, 2020

Revvity Omics, Revvity

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Sep 03, 2024

GeneDx

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Identified in individuals who did not harbor a second RYR1 variant, who had features of congenital onset RYR1-related disease (PMID: 27854218); Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 23069638, 20583297, 27854218) -

Oct 19, 2015

Eurofins Ntd Llc (ga)

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Dec 02, 2013

Genetic Services Laboratory, University of Chicago

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Mar 01, 2025

CeGaT Center for Human Genetics Tuebingen

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

RYR1: PM2, PM3, PP3, PP4 -

RYR1-related disorder

Pathogenic:2

Nov 29, 2023

PreventionGenetics, part of Exact Sciences

Significance: Likely pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

The RYR1 c.10204T>G variant is predicted to result in the amino acid substitution p.Cys3402Gly. This variant has been reported in the compound heterozygous state in an individual with congenital fiber type disproportion (Clarke et al. 2010. PubMed ID: 20583297). It has also been reported in the heterozygous state in an individual with congenital fiber type disproportion that did not have a second pathogenic variant (Punetha et al. 2016. PubMed ID: 27854218). This variant is reported in 0.0059% of alleles in individuals of European (Non-Finnish) descent in gnomAD. This variant has conflicting interpretations of pathogenicity in ClinVar of uncertain, likely pathogenic and pathogenic (https://www.ncbi.nlm.nih.gov/clinvar/variation/42098/). Based on the available evidence, we consider the RYR1 c.10204T>G (p.Cys3402Gly) variant to be likely pathogenic. -

Sep 30, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change replaces cysteine, which is neutral and slightly polar, with glycine, which is neutral and non-polar, at codon 3402 of the RYR1 protein (p.Cys3402Gly). This variant is present in population databases (rs367543058, gnomAD 0.004%). This missense change has been observed in individual(s) with autosomal recessive congenital myopathy, and congenital fiber type disproportion (CFTD) (PMID: 20583297, 27854218; internal data). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 42098). 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) indicates that this missense variant is expected to disrupt RYR1 protein function with a positive predictive value of 80%. For these reasons, this variant has been classified as Pathogenic. -

Congenital multicore myopathy with external ophthalmoplegia

Pathogenic:1

Oct 11, 2024

Victorian Clinical Genetics Services, Murdoch Childrens Research Institute

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Based on the classification scheme VCGS_Germline_v1.3.5, this variant is classified as Pathogenic. Following criteria are met: 0103 - Loss of function and gain of function are known mechanisms of disease in this gene and are associated with RYR1-related disorders (OMIM). Gain of function mechanism has been described in the context of malignant hyperthermia susceptibility 1 (MIM#145600) and autosomal dominant congenital myopathy 1A with susceptibility to malignant hyperthermia (MIM#117000). Autosomal recessive congenital myopathy 1B (MIM#255320) is associated with a loss of function mechanism (PMIDs: 27855725, 23919265). The mechanism of King-Denborough syndrome (MIM#619542) is unclear. (I) 0108 - This gene is associated with both recessive and dominant disease (OMIM). (I) 0200 - Variant is predicted to result in a missense amino acid change from cysteine to glycine. (I) 0251 - This variant is heterozygous. (I) 0304 - Variant is present in gnomAD <0.01 for a recessive condition (v4: 111 heterozygotes, 0 homozygotes). (SP) 0309 - Multiple alternative amino acid changes at the same position have been observed in gnomAD (v4) (highest allele count: 1 heterozygote, 0 homozygotes). (I) 0502 - Missense variant with conflicting in silico predictions and uninformative conservation. (I) 0604 - Variant is not located in an established domain, motif, hotspot or informative constraint region. (I) 0705 - No comparable missense variants have previous evidence for pathogenicity. (I) 0801 - This variant has strong previous evidence of pathogenicity in unrelated individuals. This variant has been classified as likely pathogenic/pathogenic by six clinical laboratories and as a VUS by three clinical laboratories in ClinVar. It has also been reported in multiple compound heterozygous individuals with features consistent with autosomal recessive congenital myopathy 1B (PMID: 20583297; personal communication) and in two heterozygous individuals with congenital fiber type disproportion that did not have a second pathogenic variant (PMID: 27854218). (SP) 1201 - Heterozygous variant detected in trans with a second pathogenic heterozygous variant (NM_000540.2:c.3899delT; p.(Phe1300Serfs*98)) in a recessive disease. (SP) 1206 - This variant has been shown to be paternally inherited (by trio analysis). (I) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign -

RYR1-related myopathy

Pathogenic:1

Feb 10, 2025

ClinGen Congenital Myopathies Variant Curation Expert Panel, ClinGen

Significance: Pathogenic

Review Status: reviewed by expert panel

Collection Method: curation

The NM_000540.3:c.10204T>G (p.Cys3402Gly) variant in RYR1 is a missense variant predicted to cause a substitution of cysteine by glycine at amino acid 3402. The computational predictor REVEL gives a score of 0.851, which is above the threshold for predicting a damaging effect on RYR1 variants (PP3). The highest population minor allele frequency in gnomAD v4.1.0 is 0.00006 (7/117872 alleles) in European (non-Finnish) population, which is higher than the ClinGen Congenital Myopathies VCEP threshold (≤0.00000697) for PM2_Supporting and lower than ClinGen Congenital Myopathies VCEP threshold (≥0.000697) for BS1, therefore no population criteria can be applied. The variant has been reported in trans with a second pathogenic RYR1 variant or a rare variant of uncertain significance in RYR1 in 10 probands with clinical features of congenital myopathy (PMID: 20583297; Synnovis internal data SCV001468505.1; Invitae internal data SCV000659742.9) (PM3_Very Strong). The variant along with another pathogenic variant in trans was identified in two siblings with congenital myopathy suggesting cosegregation (Invitae internal data) (PP1). In summary, this variant meets the criteria to be classified as pathogenic for autosomal recessive RYR1-related myopathy based on the ACMG/AMP criteria applied as specified by the ClinGen Congenital Myopathy VCEP: PM3_Very Strong, PP1, PP3 (ClinGen Congenital Myopathies VCEP Specifications 2.0.0; 2/10/2025). -

Central core myopathy

Pathogenic:1

Dec 01, 2015

Center for Genetic Medicine Research, Children's National Medical Center

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: research

- -

not specified

Uncertain:1

Aug 12, 2016

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance: Uncertain significance

Review Status: flagged submission

Collection Method: clinical testing

Variant identified in a genome or exome case(s) and assessed due to predicted null impact of the variant or pathogenic assertions in the literature or databases. Disclaimer: This variant has not undergone full assessment. The following are preliminary notes: Only reported in association with myopathy (congenital fiber type disproportion), in only 1 proband. -

Malignant hyperthermia, susceptibility to, 1

Uncertain:1

Sep 23, 2024

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 cysteine with glycine at codon 3402 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 not been reported in individuals affected with autosomal dominant malignant hyperthermia in the literature, although it is associated with other phenotype(s) (ClinVar variation ID: 42098; PMID: 20583297, 27854218). This variant has been identified in 7/262002 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. -

Congenital myopathy with fiber type disproportion

Other:1

GeneReviews

Significance: not provided

Review Status: no classification provided

Collection Method: literature only

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.82

BayesDel_addAF

Pathogenic

0.42

BayesDel_noAF

Pathogenic

0.45

CADD

Benign

DANN

Benign

0.87

DEOGEN2

Pathogenic

0.81

.;D

Eigen

Uncertain

0.28

Eigen_PC

Uncertain

0.27

FATHMM_MKL

Pathogenic

0.97

LIST_S2

Uncertain

0.94

D;D

M_CAP

Pathogenic

0.54

MetaRNN

Pathogenic

0.92

D;D

MetaSVM

Pathogenic

0.82

MutationAssessor

Benign

1.9

L;L

PrimateAI

Pathogenic

0.82

PROVEAN

Pathogenic

-6.6

D;D

REVEL

Pathogenic

0.85

Sift

Uncertain

0.0020

D;D

Polyphen

0.79

P;P

Vest4

0.90

MVP

0.95

MPC

0.38

ClinPred

0.48

GERP RS

3.6

Varity_R

0.84

gMVP

0.65

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