19-38519399-T-G

Variant summary

Our verdict is Uncertain significance. Variant got 4 ACMG points: 4P and 0B. PP2PP3_ModeratePP5

The NM_000540.3(RYR1):ā€‹c.10204T>Gā€‹(p.Cys3402Gly) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000692 in 1,604,074 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

Frequency

Genomes: š‘“ 0.000046 ( 0 hom., cov: 32)
Exomes š‘“: 0.000072 ( 0 hom. )

Consequence

RYR1
NM_000540.3 missense

Scores

11
4
3

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:8U: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]

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 4 ACMG points.

PP2
Missense variant in the RYR1 gene, where missense mutations are typically associated with disease (based on misZ statistic). The gene has 212 curated pathogenic missense variants (we use a threshold of 10). The gene has 94 curated benign missense variants. Gene score misZ: 1.918 (below the threshold of 3.09). Trascript score misZ: 3.9788 (above the threshold of 3.09). GenCC associations: The gene is linked to King-Denborough syndrome, congenital multicore myopathy with external ophthalmoplegia, autosomal recessive centronuclear myopathy, RYR1-related myopathy, lethal multiple pterygium syndrome, malignant hyperthermia of anesthesia, benign Samaritan congenital myopathy, malignant hyperthermia, susceptibility to, 1, congenital myopathy with myasthenic-like onset, central core myopathy.
PP3
MetaRNN computational evidence supports a deleterious effect, 0.917
PP5
Variant 19-38519399-T-G is Pathogenic according to our data. Variant chr19-38519399-T-G is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 42098.We mark this variant Likely_pathogenic, oryginal submissions are: {Uncertain_significance=3, Pathogenic=3, Likely_pathogenic=4, not_provided=1}. Variant chr19-38519399-T-G is described in Lovd as [Likely_pathogenic].

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
RYR1NM_000540.3 linkc.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
RYR1ENST00000359596.8 linkc.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:
7
AN:
152192
Hom.:
0
Cov.:
32
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:
5
AN:
230648
Hom.:
0
AF XY:
0.0000321
AC XY:
4
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.:
0
Cov.:
32
AF XY:
0.0000693
AC XY:
50
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:
7
AN:
152192
Hom.:
0
Cov.:
32
AF XY:
0.0000269
AC XY:
2
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.:
0
Bravo
AF:
0.0000453
ExAC
AF:
0.0000165
AC:
2

ClinVar

Significance: Conflicting classifications of pathogenicity
Submissions summary: Pathogenic:8Uncertain:3Other:1
Revision: criteria provided, conflicting classifications
LINK: link

Submissions by phenotype

not provided Pathogenic:4Uncertain:1
Aug 01, 2024
CeGaT Center for Human Genetics Tuebingen
Significance: Likely pathogenic
Review Status: criteria provided, single submitter
Collection Method: clinical testing

RYR1: PM2, PM3, PP3, PP4 -

Oct 19, 2015
Eurofins Ntd Llc (ga)
Significance: Uncertain significance
Review Status: flagged submission
Collection Method: clinical testing

- -

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) -

Dec 02, 2013
Genetic Services Laboratory, University of Chicago
Significance: Pathogenic
Review Status: criteria provided, single submitter
Collection Method: clinical testing

- -

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 -

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
D
BayesDel_noAF
Pathogenic
0.45
CADD
Benign
22
DANN
Benign
0.87
DEOGEN2
Pathogenic
0.81
.;D
Eigen
Uncertain
0.28
Eigen_PC
Uncertain
0.27
FATHMM_MKL
Pathogenic
0.97
D
LIST_S2
Uncertain
0.94
D;D
M_CAP
Pathogenic
0.54
D
MetaRNN
Pathogenic
0.92
D;D
MetaSVM
Pathogenic
0.82
D
MutationAssessor
Benign
1.9
L;L
PrimateAI
Pathogenic
0.82
D
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
T
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.

Other links and lift over

dbSNP: rs367543058; hg19: chr19-39010039; API