chr19-38494381-G-C
Variant summary
Our verdict is Uncertain significance. Variant got 2 ACMG points: 2P and 0B. PM1
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 valine with leucine at codon 2102 of the RYR1 protein, p.Val2102Leu. The maximum allele frequency for this variant among the six major gnomAD populations is NFE: 0.000018, 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), however, this variant was in cis to a second RYR1 variant that has been classified as a variant of uncertain significance (p.Arg1583Cys), for that reason PS4 was not implemented (PMID:23035052). The allele containing both variants segregated with MHS in four individuals in this family, however, since the effect of the two alleles cannot be separated PP1 was not implemented for this variant (PMID:23035052). 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 of 0.515 supports neither a pathogenic nor a benign status for this variant. This variant has been classified as a Variant of Unknown Significance. Criteria implemented: PM1. LINK:https://erepo.genome.network/evrepo/ui/classification/CA068028/MONDO:0007783/012
Frequency
Consequence
NM_000540.3 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Uncertain_significance. Variant got 2 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
RYR1 | NM_000540.3 | c.6304G>C | p.Val2102Leu | missense_variant | 39/106 | ENST00000359596.8 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
RYR1 | ENST00000359596.8 | c.6304G>C | p.Val2102Leu | missense_variant | 39/106 | 5 | NM_000540.3 | A2 | |
RYR1 | ENST00000355481.8 | c.6304G>C | p.Val2102Leu | missense_variant | 39/105 | 1 | P4 | ||
RYR1 | ENST00000599547.6 | c.6304G>C | p.Val2102Leu | missense_variant, NMD_transcript_variant | 39/80 | 2 |
Frequencies
GnomAD3 genomes ? Cov.: 31
GnomAD3 exomes AF: 0.00000807 AC: 2AN: 247692Hom.: 0 AF XY: 0.00000743 AC XY: 1AN XY: 134640
GnomAD4 exome AF: 0.00000137 AC: 2AN: 1459404Hom.: 0 Cov.: 32 AF XY: 0.00000138 AC XY: 1AN XY: 726006
GnomAD4 genome ? Cov.: 31
ClinVar
Submissions by phenotype
Malignant hyperthermia, susceptibility to, 1 Uncertain:2
Uncertain significance, criteria provided, single submitter | clinical testing | All of Us Research Program, National Institutes of Health | Jun 28, 2023 | - - |
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 valine with leucine at codon 2102 of the RYR1 protein, p.Val2102Leu. The maximum allele frequency for this variant among the six major gnomAD populations is NFE: 0.000018, 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), however, this variant was in cis to a second RYR1 variant that has been classified as a variant of uncertain significance (p.Arg1583Cys), for that reason PS4 was not implemented (PMID:23035052). The allele containing both variants segregated with MHS in four individuals in this family, however, since the effect of the two alleles cannot be separated PP1 was not implemented for this variant (PMID:23035052). 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 of 0.515 supports neither a pathogenic nor a benign status for this variant. This variant has been classified as a Variant of Unknown Significance. Criteria implemented: PM1. - |
Congenital myopathy with fiber type disproportion;C0751951:Central core myopathy;C1840365:King Denborough syndrome;C1850674:Congenital multicore myopathy with external ophthalmoplegia;C2930980:Malignant hyperthermia, susceptibility to, 1 Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Fulgent Genetics, Fulgent Genetics | Jul 26, 2021 | - - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at