rs746818096
Variant summary
Our verdict is Uncertain significance. Variant got 1 ACMG points: 2P and 1B. BP4PM1
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 methionine with lysine at codon 2101 of the RYR1 protein, p.(Met2101Lys). The maximum minor allele frequency (MAF) for this variant among the six major gnomAD populations is NFE: 0.000087, a frequency consistent with pathogenicity for MHS. However, the MAF in the Ashkenazi Jewish population is 0.0047 which is considered to be too common for a pathogenic variant causing autosomal dominantly inherited MHS. This variant has been reported in three unrelated individuals who have a personal or family history of a malignant hyperthermia reaction; all of these individuals had 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). One of these individuals had a second variant of uncertain significance in RYR1 (p.Arg1469Trp, VUS) (PMID:20681998, PMID:25735680, PMID:30236257). The high MAF in the Ashkenazi Jewish population precludes implementing PS4. No functional studies were identified for this variant. This variant resides in a region of RYR1 considered to be a hotspot for pathogenic variants that contribute to MHS, PM1 (PMID:21118704). A REVEL score <0.5 (0.392) supports a benign status for this variant, BP4. This variant has been classified as a Variant of Unknown Significance. Criteria implemented: PM1, BP4. LINK:https://erepo.genome.network/evrepo/ui/classification/CA068024/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 1 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
RYR1 | NM_000540.3 | c.6302T>A | p.Met2101Lys | missense_variant | 39/106 | ENST00000359596.8 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
RYR1 | ENST00000359596.8 | c.6302T>A | p.Met2101Lys | missense_variant | 39/106 | 5 | NM_000540.3 | A2 | |
RYR1 | ENST00000355481.8 | c.6302T>A | p.Met2101Lys | missense_variant | 39/105 | 1 | P4 | ||
RYR1 | ENST00000599547.6 | c.6302T>A | p.Met2101Lys | missense_variant, NMD_transcript_variant | 39/80 | 2 |
Frequencies
GnomAD3 genomes AF: 0.000131 AC: 20AN: 152162Hom.: 0 Cov.: 31
GnomAD3 exomes AF: 0.000238 AC: 59AN: 247564Hom.: 0 AF XY: 0.000230 AC XY: 31AN XY: 134586
GnomAD4 exome AF: 0.0000966 AC: 141AN: 1459390Hom.: 1 Cov.: 32 AF XY: 0.000110 AC XY: 80AN XY: 726004
GnomAD4 genome AF: 0.000131 AC: 20AN: 152280Hom.: 0 Cov.: 31 AF XY: 0.0000940 AC XY: 7AN XY: 74460
ClinVar
Submissions by phenotype
not provided Uncertain:4
Uncertain significance, criteria provided, single submitter | clinical testing | CeGaT Center for Human Genetics Tuebingen | Jan 01, 2023 | - - |
Uncertain significance, criteria provided, single submitter | clinical testing | Revvity Omics, Revvity | May 11, 2022 | - - |
Uncertain significance, criteria provided, single submitter | clinical testing | GeneDx | May 24, 2022 | In silico analysis supports that this missense variant does not alter protein structure/function; Identified in individuals with malignant hyperthermia in published literature, although these patients also had other RYR1 variants (Tammaro et al., 2003; Gillies et al., 2015); This variant is associated with the following publications: (PMID: 12668474, 12709367, 20681998, 25735680) - |
Uncertain significance, criteria provided, single submitter | clinical testing | PreventionGenetics, part of Exact Sciences | Dec 31, 2015 | - - |
not specified Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Women's Health and Genetics/Laboratory Corporation of America, LabCorp | Dec 05, 2023 | Variant summary: RYR1 c.6302T>A (p.Met2101Lys) results in a non-conservative amino acid change located in the Ryanodine receptor, junctional solenoid domain (IPR048581) of the encoded protein sequence. Three of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 0.00024 in 247564 control chromosomes (gnomAD). c.6302T>A has been reported in the literature in individuals affected with malignant hyperthermia susceptibility (examples: Tammaro_2003, Tammaro_2011, Gillies_2015, Miller_2018). These report(s) do not provide unequivocal conclusions about association of the variant with Myopathy, RYR1-Associated. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. The following publications have been ascertained in the context of this evaluation (PMID: 25735680, 30236257, 12709367, 20681998). Seven submitters including ClinGen Malignant Hyperthermia Susceptibility Variant Curation Expert Panel, have cited clinical-significance assessments for this variant to ClinVar after 2014 and classified the variant as VUS (n=6, includes the expert panel) and likely benign (n=1). Based on the evidence outlined above, the variant was classified as uncertain significance. - |
Congenital multicore myopathy with external ophthalmoplegia Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Illumina Laboratory Services, Illumina | Apr 28, 2017 | This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). No publications were found based on this search. Allele frequency data from public databases did not allow this variant to be ruled in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance. - |
Malignant hyperthermia, susceptibility to, 1 Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Illumina Laboratory Services, Illumina | Apr 28, 2017 | This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). No publications were found based on this search. Allele frequency data from public databases did not allow this variant to be ruled in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance. - |
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 methionine with lysine at codon 2101 of the RYR1 protein, p.(Met2101Lys). The maximum minor allele frequency (MAF) for this variant among the six major gnomAD populations is NFE: 0.000087, a frequency consistent with pathogenicity for MHS. However, the MAF in the Ashkenazi Jewish population is 0.0047 which is considered to be too common for a pathogenic variant causing autosomal dominantly inherited MHS. This variant has been reported in three unrelated individuals who have a personal or family history of a malignant hyperthermia reaction; all of these individuals had 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). One of these individuals had a second variant of uncertain significance in RYR1 (p.Arg1469Trp, VUS) (PMID:20681998, PMID:25735680, PMID:30236257). The high MAF in the Ashkenazi Jewish population precludes implementing PS4. No functional studies were identified for this variant. This variant resides in a region of RYR1 considered to be a hotspot for pathogenic variants that contribute to MHS, PM1 (PMID: 21118704). A REVEL score <0.5 (0.392) supports a benign status for this variant, BP4. This variant has been classified as a Variant of Unknown Significance. Criteria implemented: PM1, BP4. - |
RYR1-related disorder Benign:1
Likely benign, criteria provided, single submitter | clinical testing | Invitae | Jan 29, 2024 | - - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at