rs758210285

Variant summary

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

The NM_000540.3(RYR1):​c.9623C>T​(p.Pro3208Leu) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000771 in 1,556,552 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: 𝑓 0.0000066 ( 0 hom., cov: 32)
Exomes 𝑓: 0.0000078 ( 0 hom. )

Consequence

RYR1
NM_000540.3 missense

Scores

13
4
1

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:4U:2

Conservation

PhyloP100: 7.85
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 gene, where missense usually causes diseases (based on misZ statistic), RYR1. . Gene score misZ 1.918 (greater than the threshold 3.09). Trascript score misZ 3.9788 (greater than threshold 3.09). GenCC has associacion of gene with 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, 0.881
PP5
Variant 19-38516155-C-T is Pathogenic according to our data. Variant chr19-38516155-C-T is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 586415.We mark this variant Likely_pathogenic, oryginal submissions are: {Likely_pathogenic=2, Pathogenic=1, Uncertain_significance=2}.

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE Protein UniProt
RYR1NM_000540.3 linkuse as main transcriptc.9623C>T p.Pro3208Leu missense_variant 65/106 ENST00000359596.8 NP_000531.2

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Protein Appris UniProt
RYR1ENST00000359596.8 linkuse as main transcriptc.9623C>T p.Pro3208Leu missense_variant 65/1065 NM_000540.3 ENSP00000352608 A2P21817-1
RYR1ENST00000355481.8 linkuse as main transcriptc.9623C>T p.Pro3208Leu missense_variant 65/1051 ENSP00000347667 P4P21817-2
RYR1ENST00000594335.5 linkuse as main transcriptc.*366C>T 3_prime_UTR_variant, NMD_transcript_variant 25/491 ENSP00000470927
RYR1ENST00000599547.6 linkuse as main transcriptc.*382C>T 3_prime_UTR_variant, NMD_transcript_variant 64/802 ENSP00000471601

Frequencies

GnomAD3 genomes
AF:
0.00000657
AC:
1
AN:
152202
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:
0.0000941
Gnomad MID
AF:
0.00
Gnomad NFE
AF:
0.00
Gnomad OTH
AF:
0.00
GnomAD4 exome
AF:
0.00000783
AC:
11
AN:
1404350
Hom.:
0
Cov.:
31
AF XY:
0.0000130
AC XY:
9
AN XY:
693132
show subpopulations
Gnomad4 AFR exome
AF:
0.00
Gnomad4 AMR exome
AF:
0.00
Gnomad4 ASJ exome
AF:
0.00
Gnomad4 EAS exome
AF:
0.000110
Gnomad4 SAS exome
AF:
0.0000126
Gnomad4 FIN exome
AF:
0.00
Gnomad4 NFE exome
AF:
0.00000462
Gnomad4 OTH exome
AF:
0.0000172
GnomAD4 genome
AF:
0.00000657
AC:
1
AN:
152202
Hom.:
0
Cov.:
32
AF XY:
0.00
AC XY:
0
AN XY:
74360
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:
0.0000941
Gnomad4 NFE
AF:
0.00
Gnomad4 OTH
AF:
0.00
ExAC
AF:
0.00000859
AC:
1
Asia WGS
AF:
0.000289
AC:
1
AN:
3478

ClinVar

Significance: Conflicting classifications of pathogenicity
Submissions summary: Pathogenic:4Uncertain:2
Revision: criteria provided, conflicting classifications
LINK: link

Submissions by phenotype

RYR1-related disorder Pathogenic:2
Likely pathogenic, no assertion criteria providedclinical testingPreventionGenetics, part of Exact SciencesOct 19, 2023The RYR1 c.9623C>T variant is predicted to result in the amino acid substitution p.Pro3208Leu. This variant has been reported in the compound heterozygous state in two patients affected with congenital myopathy (Kalfon et al. 2022. PubMed ID: 34970863; Chang et al. 2022. PubMed ID: 35693006). Additionally, we have observed this variant alongside a second plausible causative variant in the RYR1 gene in other patients at PreventionGenetics affected with congenital myopathy. This variant is reported in 0.0052% of alleles in individuals of European (Finnish) descent in gnomAD (http://gnomad.broadinstitute.org/variant/19-39006795-C-T). This variant is interpreted as likely pathogenic. -
Pathogenic, criteria provided, single submitterclinical testingLabcorp Genetics (formerly Invitae), LabcorpJan 16, 2024This sequence change replaces proline, which is neutral and non-polar, with leucine, which is neutral and non-polar, at codon 3208 of the RYR1 protein (p.Pro3208Leu). This variant is present in population databases (rs758210285, gnomAD 0.005%). This missense change has been observed in individual(s) with clinical features of autosomal recessive RYR1-related myopathy (Invitae). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. ClinVar contains an entry for this variant (Variation ID: 586415). 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%. For these reasons, this variant has been classified as Pathogenic. -
not provided Pathogenic:1Uncertain:1
Likely pathogenic, criteria provided, single submitterclinical testingGeneDxFeb 27, 2024Not 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: 34970863, 35693006, 12668474) -
Uncertain significance, criteria provided, single submitterclinical testingAthena DiagnosticsJun 05, 2018- -
RYR1-related myopathy Pathogenic:1
Likely pathogenic, criteria provided, single submitterprovider interpretationPediatric Department, Peking University First HospitalFeb 08, 2022- -
Malignant hyperthermia, susceptibility to, 1 Uncertain:1
Uncertain significance, criteria provided, single submitterclinical testingAll of Us Research Program, National Institutes of HealthSep 05, 2023- -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Pathogenic
0.57
BayesDel_addAF
Pathogenic
0.27
D
BayesDel_noAF
Pathogenic
0.16
CADD
Benign
21
DANN
Uncertain
0.99
DEOGEN2
Pathogenic
0.82
.;D
Eigen
Pathogenic
0.77
Eigen_PC
Pathogenic
0.71
FATHMM_MKL
Pathogenic
0.98
D
LIST_S2
Pathogenic
0.98
D;D
M_CAP
Pathogenic
0.50
D
MetaRNN
Pathogenic
0.88
D;D
MetaSVM
Pathogenic
1.0
D
MutationAssessor
Uncertain
2.9
M;M
MutationTaster
Benign
1.0
D;D;D
PrimateAI
Uncertain
0.75
T
PROVEAN
Pathogenic
-6.8
D;D
REVEL
Pathogenic
0.80
Sift
Uncertain
0.0020
D;D
Polyphen
1.0
D;D
Vest4
0.77
MutPred
0.48
Gain of helix (P = 0.0425);Gain of helix (P = 0.0425);
MVP
1.0
MPC
0.31
ClinPred
1.0
D
GERP RS
4.8
Varity_R
0.56
gMVP
0.78

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: rs758210285; hg19: chr19-39006795; API