chr19-38527683-CTG-C
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Variant summary
Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PVS1PM2PP5_Very_Strong
The NM_000540.3(RYR1):βc.10725_10726delβ(p.Tyr3576ProfsTer12) variant causes a frameshift change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000000684 in 1,461,842 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Likely pathogenic (β β ). Variant results in nonsense mediated mRNA decay.
Frequency
Genomes: not found (cov: 31)
Exomes π: 6.8e-7 ( 0 hom. )
Consequence
RYR1
NM_000540.3 frameshift
NM_000540.3 frameshift
Scores
Not classified
Clinical Significance
Conservation
PhyloP100: 7.78
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 18 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 19-38527683-CTG-C is Pathogenic according to our data. Variant chr19-38527683-CTG-C is described in ClinVar as [Likely_pathogenic]. Clinvar id is 436631.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
RYR1 | NM_000540.3 | c.10725_10726del | p.Tyr3576ProfsTer12 | frameshift_variant | 73/106 | ENST00000359596.8 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
RYR1 | ENST00000359596.8 | c.10725_10726del | p.Tyr3576ProfsTer12 | frameshift_variant | 73/106 | 5 | NM_000540.3 | A2 | |
ENST00000597015.1 | n.326_327del | non_coding_transcript_exon_variant | 2/3 | 4 |
Frequencies
GnomAD3 genomes Cov.: 31
GnomAD3 genomes
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31
GnomAD4 exome AF: 6.84e-7 AC: 1AN: 1461842Hom.: 0 AF XY: 0.00 AC XY: 0AN XY: 727220
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GnomAD4 genome Cov.: 31
GnomAD4 genome
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31
ClinVar
Significance: Pathogenic/Likely pathogenic
Submissions summary: Pathogenic:3
Revision: criteria provided, multiple submitters, no conflicts
LINK: link
Submissions by phenotype
RYR1-related disorder Pathogenic:2
Pathogenic, criteria provided, single submitter | clinical testing | Invitae | Feb 24, 2020 | Loss-of-function variants in RYR1 are known to be pathogenic (PMID: 20583297, 20839240, 23919265, 28818389). This variant has not been reported in the literature in individuals with RYR1-related conditions. ClinVar contains an entry for this variant (Variation ID: 436631). This variant is not present in population databases (ExAC no frequency). This sequence change creates a premature translational stop signal (p.Tyr3576Profs*12) in the RYR1 gene. It is expected to result in an absent or disrupted protein product. For these reasons, this variant has been classified as Pathogenic. - |
Likely pathogenic, criteria provided, single submitter | clinical testing | PreventionGenetics, part of Exact Sciences | Nov 03, 2022 | The RYR1 c.10725_10726delGT variant is predicted to result in a frameshift and premature protein termination (p.Tyr3576Profs*12). To our knowledge, this variant has not been reported in the literature. This variant has not been reported in a large population database (http://gnomad.broadinstitute.org), indicating this variant is rare. Frameshift variants in RYR1 are expected to be pathogenic for autosomal recessive RYR1-related myopathies. This variant is interpreted as likely pathogenic for autosomal recessive RYR1-disorders. Of note, it is uncertain if this variant would be disease causing for autosomal dominant RYR1-disorders. - |
not provided Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Genetic Services Laboratory, University of Chicago | May 30, 2017 | - - |
Computational scores
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SpliceAI score (max)
Details are displayed if max score is > 0.2
Find out detailed SpliceAI scores and Pangolin per-transcript scores at