rs1555805797

Variant summary

Our verdict is Likely pathogenic. Variant got 8 ACMG points: 8P and 0B. PM1PM2PP2PP3_ModeratePP5

The NM_000540.3(RYR1):​c.15017G>A​(p.Gly5006Asp) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. 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: not found (cov: 32)

Consequence

RYR1
NM_000540.3 missense

Scores

15
1
2

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:1U: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 Likely_pathogenic. Variant got 8 ACMG points.

PM1
In a topological_domain Cytoplasmic (size 96) in uniprot entity RYR1_HUMAN there are 7 pathogenic changes around while only 0 benign (100%) in NM_000540.3
PM2
Very rare variant in population databases, with high coverage;
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, 0.921
PP5
Variant 19-38586572-G-A is Pathogenic according to our data. Variant chr19-38586572-G-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 544378.We mark this variant Likely_pathogenic, oryginal submissions are: {Uncertain_significance=1, Pathogenic=1}.

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE Protein UniProt
RYR1NM_000540.3 linkuse as main transcriptc.15017G>A p.Gly5006Asp missense_variant 105/106 ENST00000359596.8 NP_000531.2

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Protein Appris UniProt
RYR1ENST00000359596.8 linkuse as main transcriptc.15017G>A p.Gly5006Asp missense_variant 105/1065 NM_000540.3 ENSP00000352608 A2P21817-1

Frequencies

GnomAD3 genomes
Cov.:
32
GnomAD4 exome
Cov.:
31
GnomAD4 genome
Cov.:
32

ClinVar

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

Submissions by phenotype

RYR1-related disorder Pathogenic:1
Pathogenic, criteria provided, single submitterclinical testingLabcorp Genetics (formerly Invitae), LabcorpMar 23, 2023This variant disrupts the p.Gly5006 amino acid residue in RYR1. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 27447704; Invitae). 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. 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: 544378). This missense change has been observed in individual(s) with clinical features of autosomal dominant RYR1-related conditions (Invitae). It has also been observed to segregate with disease in related individuals. This variant is not present in population databases (gnomAD no frequency). This sequence change replaces glycine, which is neutral and non-polar, with aspartic acid, which is acidic and polar, at codon 5006 of the RYR1 protein (p.Gly5006Asp). -
not provided Uncertain:1
Uncertain significance, criteria provided, single submitterclinical testingRevvity Omics, RevvitySep 20, 2022- -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Pathogenic
0.99
BayesDel_addAF
Pathogenic
0.45
D
BayesDel_noAF
Pathogenic
0.41
CADD
Uncertain
24
DANN
Benign
0.93
DEOGEN2
Pathogenic
0.87
.;D
Eigen
Pathogenic
0.89
Eigen_PC
Pathogenic
0.76
FATHMM_MKL
Uncertain
0.96
D
LIST_S2
Pathogenic
0.98
D;D
M_CAP
Pathogenic
0.87
D
MetaRNN
Pathogenic
0.92
D;D
MetaSVM
Pathogenic
1.1
D
MutationAssessor
Pathogenic
3.4
.;M
MutationTaster
Benign
1.0
D;D;D
PrimateAI
Pathogenic
0.91
D
PROVEAN
Pathogenic
-5.8
D;D
REVEL
Pathogenic
0.85
Sift
Pathogenic
0.0
D;D
Polyphen
1.0
D;D
Vest4
0.79
MutPred
0.44
.;Gain of phosphorylation at T5005 (P = 0.1274);
MVP
1.0
MPC
0.75
ClinPred
1.0
D
GERP RS
4.6
Varity_R
0.91
gMVP
0.92

Splicing

Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
0.020
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: rs1555805797; hg19: chr19-39077212; API