rs376149732
Variant summary
Our verdict is Likely benign. Variant got -1 ACMG points: 1P and 2B. BS2_SupportingBS3_SupportingPS4_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 sequence variant predicts a substitution of proline with leucine at codon 816 of the RYR1 protein, p.(Pro816Leu). The maximum allele frequency for this variant among the six major gnomAD populations is NFE: .000046, a frequency consistent with pathogenicity for MHS. 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:30236257). This variant has been identified in one individual with a negative IVCT/CHCT results, BS2_Moderate (The UK (Leeds) MH Unit). Functional studies in HEK293 cells do not show a significant increased sensitivity to RYR1 agonists BS3_Supporting (PMID:31903994). This variant does not reside in a hotspot for pathogenic variants that contribute to MHS. A REVEL score of .758 supports neither a pathogenic nor a benign status for this variant. Based on using Bayes to combine criteria this variant is assessed as Likely Benign, (PMID:29300386). Criteria implemented: PS4_Supporting, BS2_Moderate, BS3_Supporting. LINK:https://erepo.genome.network/evrepo/ui/classification/CA063246/MONDO:0018493/012
Frequency
Consequence
NM_000540.3 missense
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 | UniProt |
---|---|---|---|---|---|---|---|
RYR1 | NM_000540.3 | c.2447C>T | p.Pro816Leu | missense_variant | 20/106 | ENST00000359596.8 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
RYR1 | ENST00000359596.8 | c.2447C>T | p.Pro816Leu | missense_variant | 20/106 | 5 | NM_000540.3 | A2 | |
RYR1 | ENST00000355481.8 | c.2447C>T | p.Pro816Leu | missense_variant | 20/105 | 1 | P4 | ||
RYR1 | ENST00000599547.6 | c.2447C>T | p.Pro816Leu | missense_variant, NMD_transcript_variant | 20/80 | 2 |
Frequencies
GnomAD3 genomes ? AF: 0.0000131 AC: 2AN: 152242Hom.: 0 Cov.: 33
GnomAD3 exomes AF: 0.0000159 AC: 4AN: 251486Hom.: 0 AF XY: 0.00000736 AC XY: 1AN XY: 135918
GnomAD4 exome AF: 0.0000725 AC: 106AN: 1461882Hom.: 0 Cov.: 32 AF XY: 0.0000743 AC XY: 54AN XY: 727244
GnomAD4 genome ? AF: 0.0000131 AC: 2AN: 152242Hom.: 0 Cov.: 33 AF XY: 0.0000134 AC XY: 1AN XY: 74374
ClinVar
Submissions by phenotype
RYR1-related disorder Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Invitae | Jul 12, 2022 | This sequence change replaces proline, which is neutral and non-polar, with leucine, which is neutral and non-polar, at codon 816 of the RYR1 protein (p.Pro816Leu). This variant is present in population databases (rs376149732, gnomAD 0.006%). This missense change has been observed in individual(s) with clinical features of RYR1-related conditions (PMID: 31903994, 31994743). ClinVar contains an entry for this variant (Variation ID: 478213). 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. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. - |
Malignant hyperthermia, susceptibility to, 1 Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Color Diagnostics, LLC DBA Color Health | Apr 20, 2023 | This missense variant replaces proline with leucine at codon 816 of the RYR1 protein. Computational prediction suggests that this variant may have deleterious impact on protein structure and function (internally defined REVEL score threshold >= 0.7, PMID: 27666373). A functional study has shown that this variant does not increase sensitivity to 4-CmC in HEK293 cells (PMID: 31903994). This variant has been reported in families/individuals affected with malignant hyperthermia susceptibility and in an individual with a negative in vitro contracture test (PMID: 30236257, 31903994, ClinVar: SCV002047609.1). This variant has been identified in 6/282882 chromosomes in the general population by the Genome Aggregation Database (gnomAD). The available evidence is insufficient to determine the role of this variant in disease conclusively. Therefore, this variant is classified as a Variant of Uncertain Significance. - |
Malignant hyperthermia of anesthesia Benign:1
Likely benign, reviewed by expert panel | curation | ClinGen Malignant Hyperthermia Susceptibility Variant Curation Expert Panel, ClinGen | Nov 09, 2021 | 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 proline with leucine at codon 816 of the RYR1 protein, p.(Pro816Leu). The maximum allele frequency for this variant among the six major gnomAD populations is NFE: .000046, a frequency consistent with pathogenicity for MHS. 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:30236257). This variant has been identified in one individual with a negative IVCT/CHCT results, BS2_Moderate (The UK (Leeds) MH Unit). Functional studies in HEK293 cells do not show a significant increased sensitivity to RYR1 agonists BS3_Supporting (PMID: 31903994). This variant does not reside in a hotspot for pathogenic variants that contribute to MHS. A REVEL score of .758 supports neither a pathogenic nor a benign status for this variant. Based on using Bayes to combine criteria this variant is assessed as Likely Benign, (PMID: 29300386). Criteria implemented: PS4_Supporting, BS2_Moderate, BS3_Supporting. - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at