19-38494565-G-T
Variant summary
Our verdict is Likely pathogenic. Variant got 6 ACMG points: 6P and 0B. PM5PS4_SupportingPM1_SupportingPP3_Moderate
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 arginine with leucine at codon 2163 of the RYR1 protein, p.(Arg2163Leu). This variant was not present in a large population database (gnomAD) at the time this variant was interpreted. This variant has been reported in two individuals with personal or family history of an MH episode without positive in vitro contracture test (IVCT) or caffeine halothane contracture test (CHCT) results, PS4_Sup (PMID:32919876, personal communication). No functional studies were identified for this variant. Another variant assessed as pathogenic occurs at this codon, p.(Arg2163His), PM5. This variant resides in a region of RYR1 considered to be a hotspot for pathogenic variants that contribute to MHS, use PM1_Supporting to avoid overweighting with PM5 (PMID:21118704). A REVEL score >0.85 (0.926) supports a pathogenic status for this variant, PP3_Moderate. This variant has been classified as a Likely Pathogenic. Criteria implemented: PS4_Sup, PM1_Sup, PM5, PP3_Moderate. LINK:https://erepo.genome.network/evrepo/ui/classification/CA405664296/MONDO:0018493/012
Frequency
Consequence
NM_000540.3 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Likely_pathogenic. Variant got 6 ACMG points.
Transcripts
RefSeq
Ensembl
| Gene | Transcript | HGVSc | HGVSp | Effect | Exon rank | TSL | MANE | Protein | Appris | UniProt |
|---|---|---|---|---|---|---|---|---|---|---|
| RYR1 | ENST00000359596.8 | c.6488G>T | p.Arg2163Leu | missense_variant | Exon 39 of 106 | 5 | NM_000540.3 | ENSP00000352608.2 | ||
| RYR1 | ENST00000355481.8 | c.6488G>T | p.Arg2163Leu | missense_variant | Exon 39 of 105 | 1 | ENSP00000347667.3 | |||
| RYR1 | ENST00000599547.6 | n.6488G>T | non_coding_transcript_exon_variant | Exon 39 of 80 | 2 | ENSP00000471601.2 |
Frequencies
GnomAD3 genomes
GnomAD4 exome Cov.: 32
GnomAD4 genome
ClinVar
Submissions by phenotype
not provided Pathogenic:2
Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 12668474, 33767344, 37496383, 32919876, 12124989, 9497245) -
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RYR1-related disorder Pathogenic:1
This sequence change replaces arginine, which is basic and polar, with leucine, which is neutral and non-polar, at codon 2163 of the RYR1 protein (p.Arg2163Leu). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with autosomal dominant malignant hyperthermia (PMID: 32919876). ClinVar contains an entry for this variant (Variation ID: 590571). Invitae Evidence Modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) indicates that this missense variant is expected to disrupt RYR1 protein function with a positive predictive value of 95%. This variant disrupts the p.Arg2163 amino acid residue in RYR1. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 9497245, 9873004, 12124989, 12732639). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic. -
Malignant hyperthermia of anesthesia Pathogenic:1
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 arginine with leucine at codon 2163 of the RYR1 protein, p.(Arg2163Leu). This variant was not present in a large population database (gnomAD) at the time this variant was interpreted. This variant has been reported in two individuals with personal or family history of an MH episode without positive in vitro contracture test (IVCT) or caffeine halothane contracture test (CHCT) results, PS4_Sup (PMID: 32919876, personal communication). No functional studies were identified for this variant. Another variant assessed as pathogenic occurs at this codon, p.(Arg2163His), PM5. This variant resides in a region of RYR1 considered to be a hotspot for pathogenic variants that contribute to MHS, use PM1_Supporting to avoid overweighting with PM5 (PMID: 21118704). A REVEL score >0.85 (0.926) supports a pathogenic status for this variant, PP3_Moderate. This variant has been classified as a Likely Pathogenic. Criteria implemented: PS4_Sup, PM1_Sup, PM5, PP3_Moderate. -
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at