rs193922853
Variant summary
Our verdict is Uncertain significance. Variant got 0 ACMG points: 0P and 0B.
This summary comes from the ClinGen Evidence Repository: This pathogenicity assessment is relevant only for malignant hyperthermia susceptibility (MHS) inherited in an autosomal dominant pattern. Variants in RYR1 can also cause other myopathies inherited in an autosomal dominant pattern or in an autosomal recessive pattern. Some of these disorders may predispose individuals to malignant hyperthermia. RYR1 variants may also contribute to a malignant hyperthermia reaction in combination with other genetic and non-genetic factors and the clinician needs to consider such factors in making management decisions.This sequence variant predicts a substitution of glutamic acid with valine at codon 4283 of the RYR1 protein, p.(Glu4283Val). This variant was not present in a large population database (gnomAD) at the time this variant was interpreted. This variant has been reported in one individual with a personal or family history of a malignant hyperthermia reaction, a second variant of uncertain significance, p.(Val218Ile), was also identified. This individual did not have an in vitro contracture test (IVCT) or a caffeine halothane contracture test (CHCT) result, PS4 was not implemented (PMID:16732084). No functional studies were identified for this variant. This variant does not reside in a hotspot for pathogenic variants that contribute to MHS. A REVEL score of 0.561 supports neither a pathogenic nor a benign status for this variant. This variant has been classified as a Variant of Unknown Significance. Criteria implemented: none. LINK:https://erepo.genome.network/evrepo/ui/classification/CA024011/MONDO:0018493/012
Frequency
Consequence
NM_000540.3 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Uncertain_significance. Variant got 0 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
RYR1 | NM_000540.3 | c.12848A>T | p.Glu4283Val | missense_variant | 91/106 | ENST00000359596.8 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
RYR1 | ENST00000359596.8 | c.12848A>T | p.Glu4283Val | missense_variant | 91/106 | 5 | NM_000540.3 | A2 |
Frequencies
GnomAD3 genomes ? AF: 0.00000685 AC: 1AN: 145888Hom.: 0 Cov.: 32
GnomAD4 exome AF: 0.00000809 AC: 8AN: 989056Hom.: 0 Cov.: 30 AF XY: 0.00000643 AC XY: 3AN XY: 466554
GnomAD4 genome ? AF: 0.00000685 AC: 1AN: 145888Hom.: 0 Cov.: 32 AF XY: 0.0000141 AC XY: 1AN XY: 71052
ClinVar
Submissions by phenotype
Malignant hyperthermia of anesthesia Uncertain:1
Uncertain significance, reviewed by expert panel | curation | ClinGen Malignant Hyperthermia Susceptibility Variant Curation Expert Panel, ClinGen | Apr 06, 2023 | This pathogenicity assessment is relevant only for malignant hyperthermia susceptibility (MHS) inherited in an autosomal dominant pattern. Variants in RYR1 can also cause other myopathies inherited in an autosomal dominant pattern or in an autosomal recessive pattern. Some of these disorders may predispose individuals to malignant hyperthermia. RYR1 variants may also contribute to a malignant hyperthermia reaction in combination with other genetic and non-genetic factors and the clinician needs to consider such factors in making management decisions. This sequence variant predicts a substitution of glutamic acid with valine at codon 4283 of the RYR1 protein, p.(Glu4283Val). This variant was not present in a large population database (gnomAD) at the time this variant was interpreted. This variant has been reported in one individual with a personal or family history of a malignant hyperthermia reaction, a second variant of uncertain significance, p.(Val218Ile), was also identified. This individual did not have an in vitro contracture test (IVCT) or a caffeine halothane contracture test (CHCT) result, PS4 was not implemented (PMID: 16732084). No functional studies were identified for this variant. This variant does not reside in a hotspot for pathogenic variants that contribute to MHS. A REVEL score of 0.561 supports neither a pathogenic nor a benign status for this variant. This variant has been classified as a Variant of Unknown Significance. Criteria implemented: none. - |
not provided Other:1
not provided, no classification provided | literature only | Leiden Muscular Dystrophy (RYR1) | - | - - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at