19-38440796-A-G
Variant summary
Our verdict is Pathogenic. Variant got 17 ACMG points: 17P and 0B. PM1PM2PP2PP3_StrongPP5_Very_Strong
The NM_000540.3(RYR1):c.97A>G(p.Lys33Glu) 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 Likely pathogenic (★★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. K33Q) 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 17 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
RYR1 | NM_000540.3 | c.97A>G | p.Lys33Glu | missense_variant | 2/106 | ENST00000359596.8 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
RYR1 | ENST00000359596.8 | c.97A>G | p.Lys33Glu | missense_variant | 2/106 | 5 | NM_000540.3 | A2 | |
RYR1 | ENST00000355481.8 | c.97A>G | p.Lys33Glu | missense_variant | 2/105 | 1 | P4 | ||
RYR1 | ENST00000599547.6 | c.97A>G | p.Lys33Glu | missense_variant, NMD_transcript_variant | 2/80 | 2 |
Frequencies
GnomAD3 genomes ? Cov.: 32
GnomAD4 exome Cov.: 31
GnomAD4 genome ? Cov.: 32
ClinVar
Submissions by phenotype
not provided Uncertain:1Other:1
Uncertain significance, criteria provided, single submitter | clinical testing | PreventionGenetics, part of Exact Sciences | Nov 19, 2013 | - - |
not provided, no classification provided | literature only | Leiden Muscular Dystrophy (RYR1) | - | - - |
Malignant hyperthermia, susceptibility to, 1 Pathogenic:1
Likely pathogenic, 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 lysine with glutamic acid at codon 33 of the RYR1 protein, p.(Lys33Glu). This variant was not present in a large population database (gnomAD) at the time this variant was interpreted. This variant has been reported in an individual diagnosed with King-Denborough syndrome with a personal history of an MH episode and a positive caffeine halothane contracture test (CHCT) result, PS4_Supporting (PMID:18765655). In this individual the variant was determined to be de novo without confirmed parentage PM6_Supporting. 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 >0.85 (0.92) supports a pathogenic status for this variant, PP3_Moderate. This variant has been classified as Likely Pathogenic: PM6_Supporting, PS4_Supporting, PM1, PP3_Moderate. - |
King Denborough syndrome Pathogenic:1
Pathogenic, no assertion criteria provided | literature only | OMIM | Sep 02, 2008 | - - |
RYR1-related disorder Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Invitae | Apr 11, 2023 | 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. 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. ClinVar contains an entry for this variant (Variation ID: 55831). This missense change has been observed in individual(s) with autosomal dominant RYR1-related conditions (PMID: 18765655). This variant is not present in population databases (gnomAD no frequency). This sequence change replaces lysine, which is basic and polar, with glutamic acid, which is acidic and polar, at codon 33 of the RYR1 protein (p.Lys33Glu). - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at