rs1555785906
Positions:
Variant summary
Our verdict is Pathogenic. Variant got 12 ACMG points: 12P and 0B. PVS1PM2PP5_Moderate
The NM_000540.3(RYR1):c.8812dup(p.Thr2938AsnfsTer5) variant causes a frameshift change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Pathogenic (★). Variant results in nonsense mediated mRNA decay.
Frequency
Genomes: not found (cov: 31)
Consequence
RYR1
NM_000540.3 frameshift
NM_000540.3 frameshift
Scores
Not classified
Clinical Significance
Conservation
PhyloP100: 1.73
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]
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ACMG classification
Classification made for transcript
Verdict is Pathogenic. Variant got 12 ACMG points.
PVS1
?
Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.
PM2
?
Very rare variant in population databases, with high coverage;
PP5
?
Variant 19-38506947-T-TA is Pathogenic according to our data. Variant chr19-38506947-T-TA is described in ClinVar as [Pathogenic]. Clinvar id is 544385.Status of the report is criteria_provided_single_submitter, 1 stars.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
RYR1 | NM_000540.3 | c.8812dup | p.Thr2938AsnfsTer5 | frameshift_variant | 57/106 | ENST00000359596.8 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
RYR1 | ENST00000359596.8 | c.8812dup | p.Thr2938AsnfsTer5 | frameshift_variant | 57/106 | 5 | NM_000540.3 | A2 | |
RYR1 | ENST00000355481.8 | c.8812dup | p.Thr2938AsnfsTer5 | frameshift_variant | 57/105 | 1 | P4 | ||
RYR1 | ENST00000594335.5 | c.2264dup | p.Thr756AsnfsTer5 | frameshift_variant, NMD_transcript_variant | 18/49 | 1 | |||
RYR1 | ENST00000599547.6 | c.8812dup | p.Thr2938AsnfsTer5 | frameshift_variant, NMD_transcript_variant | 57/80 | 2 |
Frequencies
GnomAD3 genomes ? Cov.: 31
GnomAD3 genomes
?
Cov.:
31
GnomAD4 exome Cov.: 45
GnomAD4 exome
Cov.:
45
GnomAD4 genome ? Cov.: 31
GnomAD4 genome
?
Cov.:
31
ClinVar
Significance: Pathogenic
Submissions summary: Pathogenic:1
Revision: criteria provided, single submitter
LINK: link
Submissions by phenotype
RYR1-related disorder Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Invitae | Aug 04, 2023 | This sequence change creates a premature translational stop signal (p.Thr2938Asnfs*5) in the RYR1 gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in RYR1 are known to be pathogenic (PMID: 23919265, 25960145, 28818389, 30611313). This variant is not present in population databases (gnomAD no frequency). This variant has not been reported in the literature in individuals affected with RYR1-related conditions. ClinVar contains an entry for this variant (Variation ID: 544385). For these reasons, this variant has been classified as Pathogenic. - |
Computational scores
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Name
Calibrated prediction
Score
Prediction
Splicing
Name
Calibrated prediction
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Prediction
SpliceAI score (max)
Details are displayed if max score is > 0.2
Find out detailed SpliceAI scores and Pangolin per-transcript scores at