rs193922877
Variant summary
Our verdict is Likely benign. Variant got -1 ACMG points: 1P and 2B. BS2_SupportingPS4_SupportingBS3_Supporting
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 frameshift variant, p.Gln4837Argfs*3, predicts the substitution of glutamine with arginine at codon 4837 and a premature stop codon at position 3 of the new reading frame. This variant was not present in a large population database (gnomAD) at the time this variant was interpreted. This variant has been reported in an individual with a personal or family history of an MH episode and a positive in vitro contracture test (IVCT) or caffeine halothane contracture test (CHCT) result (if the proband was unavailable for testing, a positive diagnostic test result in a mutation-positive relative was counted), PS4_Supporting (PMID:17293538). Two relatives of this individual were shown to be heterozygous for the variant and IVCT negative, BS2_Moderate was implemented. This variant predicts a loss of function due to nonsense mediated decay, loss of function variants are not expected to cause MH. Experiments expressing this variant in HEK293 cells did not demonstrate NMD as determined by protein expression on a Western blot. Expression of this variant alone showed no calcium release upon stimulation with caffeine, when the variant was transfected with wild-type RYR1 the EC50 was comparable to that observed in cells expressing wild-type RYR1 alone, BS3_Supporting was applied (PMID:17293538). Based on using Bayes to combine criteria this variant is assessed as Likely Benign, (PMID:29300386), (relevant only for malignant hyperthermia susceptibility (MHS) inherited in an autosomal dominant pattern). Criteria implemented: PS4_Supporting, BS2_Moderate, BS3_Supporting. LINK:https://erepo.genome.network/evrepo/ui/classification/CA024161/MONDO:0018493/012
Frequency
Consequence
NM_000540.3 frameshift, splice_region
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Likely_benign. Variant got -1 ACMG points.
Transcripts
RefSeq
| Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | Protein | UniProt |
|---|---|---|---|---|---|---|---|---|
| RYR1 | NM_000540.3 | c.14510delA | p.Gln4837fs | frameshift_variant, splice_region_variant | 100/106 | ENST00000359596.8 | NP_000531.2 |
Ensembl
| Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Protein | Appris | UniProt |
|---|---|---|---|---|---|---|---|---|---|---|
| RYR1 | ENST00000359596.8 | c.14510delA | p.Gln4837fs | frameshift_variant, splice_region_variant | 100/106 | 5 | NM_000540.3 | ENSP00000352608.2 |
Frequencies
GnomAD3 genomes
GnomAD4 exome Cov.: 33
GnomAD4 genome
ClinVar
Submissions by phenotype
Malignant hyperthermia of anesthesia Benign:1
| Likely benign, reviewed by expert panel | curation | ClinGen Malignant Hyperthermia Susceptibility Variant Curation Expert Panel, ClinGen | Mar 14, 2022 | 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 frameshift variant, p.Gln4837Argfs*3, predicts the substitution of glutamine with arginine at codon 4837 and a premature stop codon at position 3 of the new reading frame. This variant was not present in a large population database (gnomAD) at the time this variant was interpreted. This variant has been reported in an individual with a personal or family history of an MH episode and a positive in vitro contracture test (IVCT) or caffeine halothane contracture test (CHCT) result (if the proband was unavailable for testing, a positive diagnostic test result in a mutation-positive relative was counted), PS4_Supporting (PMID:17293538). Two relatives of this individual were shown to be heterozygous for the variant and IVCT negative, BS2_Moderate was implemented. This variant predicts a loss of function due to nonsense mediated decay, loss of function variants are not expected to cause MH. Experiments expressing this variant in HEK293 cells did not demonstrate NMD as determined by protein expression on a Western blot. Expression of this variant alone showed no calcium release upon stimulation with caffeine, when the variant was transfected with wild-type RYR1 the EC50 was comparable to that observed in cells expressing wild-type RYR1 alone, BS3_Supporting was applied (PMID:17293538). Based on using Bayes to combine criteria this variant is assessed as Likely Benign, (PMID: 29300386), (relevant only for malignant hyperthermia susceptibility (MHS) inherited in an autosomal dominant pattern). Criteria implemented: PS4_Supporting, BS2_Moderate, BS3_Supporting. - |
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