rs193922888
Variant summary
Our verdict is Pathogenic. Variant got 11 ACMG points: 11P and 0B. PM1PM2PM5PP2PP3_Strong
The NM_000540.3(RYR1):c.14680G>A(p.Ala4894Thr) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. A4894V) has been classified as Uncertain significance.
Frequency
Consequence
NM_000540.3 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Pathogenic. Variant got 11 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
RYR1 | NM_000540.3 | c.14680G>A | p.Ala4894Thr | missense_variant | 102/106 | ENST00000359596.8 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
RYR1 | ENST00000359596.8 | c.14680G>A | p.Ala4894Thr | missense_variant | 102/106 | 5 | NM_000540.3 | A2 |
Frequencies
GnomAD3 genomes ? Cov.: 29
GnomAD4 exome Cov.: 31
GnomAD4 genome ? Cov.: 29
ClinVar
Submissions by phenotype
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 alanine with threonine at codon 4894 of the RYR1 protein, p.Ala4894Thr. This variant was not present in a large population database (gnomAD) at the time this variant was interpreted. This variant was reported in an individual with a personal or family history of an MH episode without a positive in vitro contracture test (IVCT) or caffeine halothane contracture test (CHCT) result (PMID:16732084), PS4 was not met. Functional study in HEK293 cells shows an increased sensitivity to RYR1 agonists, PS3_Moderate (PMID:21926372, PMID:33490280). This variant resides in a region of RYR1 considered to be a hotspot for pathogenic variants that contribute to MHS, PM1_Supporting (PMID: 21118704). A REVEL score >0.85 (0.922) supports a pathogenic status for this variant, PP3_Moderate. This variant has been classified as a Variant of Uncertain Significance. Criteria implemented: PS3_Moderate, PM1_Supporting, PP3_Moderate. - |
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