rs1555783257

Variant summary

Our verdict is Uncertain significance. Variant got 3 ACMG points: 3P and 0B. PM2PP2

The NM_000540.3(RYR1):​c.7054G>T​(p.Val2352Leu) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: not found (cov: 32)
Exomes 𝑓: 0.0 ( 0 hom. )
Failed GnomAD Quality Control

Consequence

RYR1
NM_000540.3 missense

Scores

4
8
6

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 9.99
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 3 ACMG points.

PM2
Very rare variant in population databases, with high coverage;
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.

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
RYR1NM_000540.3 linkc.7054G>T p.Val2352Leu missense_variant Exon 44 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.7054G>T p.Val2352Leu missense_variant Exon 44 of 106 5 NM_000540.3 ENSP00000352608.2 P21817-1
RYR1ENST00000355481.8 linkc.7054G>T p.Val2352Leu missense_variant Exon 44 of 105 1 ENSP00000347667.3 P21817-2
RYR1ENST00000594335.5 linkn.505G>T non_coding_transcript_exon_variant Exon 5 of 49 1 ENSP00000470927.2 M0R014
RYR1ENST00000599547.6 linkn.7054G>T non_coding_transcript_exon_variant Exon 44 of 80 2 ENSP00000471601.2 M0R127

Frequencies

GnomAD3 genomes
Cov.:
32
GnomAD4 exome
Data not reliable, filtered out with message: AC0
AF:
0.00
AC:
0
AN:
1446880
Hom.:
0
Cov.:
33
AF XY:
0.00
AC XY:
0
AN XY:
720252
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:
0.00
Gnomad4 OTH exome
AF:
0.00
GnomAD4 genome
Cov.:
32

ClinVar

Significance: Uncertain significance
Submissions summary: Uncertain:1
Revision: criteria provided, single submitter
LINK: link

Submissions by phenotype

RYR1-related disorder Uncertain:1
Aug 24, 2021
Labcorp Genetics (formerly Invitae), Labcorp
Significance: Uncertain significance
Review Status: criteria provided, single submitter
Collection Method: clinical testing

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Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Pathogenic
0.69
BayesDel_addAF
Uncertain
0.16
D
BayesDel_noAF
Uncertain
-0.010
CADD
Benign
23
DANN
Benign
0.95
DEOGEN2
Uncertain
0.71
.;D
Eigen
Benign
-0.011
Eigen_PC
Benign
0.12
FATHMM_MKL
Pathogenic
1.0
D
LIST_S2
Pathogenic
0.98
D;D
M_CAP
Uncertain
0.16
D
MetaRNN
Uncertain
0.48
T;T
MetaSVM
Uncertain
0.29
D
MutationAssessor
Benign
0.20
N;N
PrimateAI
Pathogenic
0.82
D
PROVEAN
Uncertain
-2.4
N;N
REVEL
Uncertain
0.58
Sift
Benign
0.99
T;T
Polyphen
0.99
D;B
Vest4
0.73
MutPred
0.59
Loss of disorder (P = 0.1959);Loss of disorder (P = 0.1959);
MVP
0.85
MPC
0.30
ClinPred
0.77
D
GERP RS
4.0
Varity_R
0.35
gMVP
0.82

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: rs1555783257; hg19: chr19-38990301; API