rs578234912
Variant summary
Our verdict is Uncertain significance. Variant got 2 ACMG points: 3P and 1B. PM1PP2BP4
The NM_000540.3(RYR1):c.3352G>A(p.Glu1118Lys) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000712 in 1,614,144 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign 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. E1118G) has been classified as Uncertain significance.
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.3352G>A | p.Glu1118Lys | missense_variant | 25/106 | ENST00000359596.8 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
RYR1 | ENST00000359596.8 | c.3352G>A | p.Glu1118Lys | missense_variant | 25/106 | 5 | NM_000540.3 | A2 | |
RYR1 | ENST00000355481.8 | c.3352G>A | p.Glu1118Lys | missense_variant | 25/105 | 1 | P4 | ||
RYR1 | ENST00000594111.1 | n.445G>A | non_coding_transcript_exon_variant | 2/2 | 2 | ||||
RYR1 | ENST00000599547.6 | c.3352G>A | p.Glu1118Lys | missense_variant, NMD_transcript_variant | 25/80 | 2 |
Frequencies
GnomAD3 genomes ? AF: 0.0000591 AC: 9AN: 152200Hom.: 0 Cov.: 32
GnomAD3 exomes AF: 0.0000478 AC: 12AN: 251212Hom.: 0 AF XY: 0.0000515 AC XY: 7AN XY: 135828
GnomAD4 exome AF: 0.0000725 AC: 106AN: 1461826Hom.: 0 Cov.: 31 AF XY: 0.0000674 AC XY: 49AN XY: 727216
GnomAD4 genome ? AF: 0.0000591 AC: 9AN: 152318Hom.: 0 Cov.: 32 AF XY: 0.000107 AC XY: 8AN XY: 74480
ClinVar
Submissions by phenotype
RYR1-related disorder Uncertain:2
Uncertain significance, criteria provided, single submitter | clinical testing | PreventionGenetics, part of Exact Sciences | Nov 18, 2022 | The RYR1 c.3352G>A variant is predicted to result in the amino acid substitution p.Glu1118Lys. To our knowledge, this variant has not been reported in the literature. This variant is reported in 0.016% of alleles in individuals of East Asian descent in gnomAD (http://gnomad.broadinstitute.org/variant/19-38958423-G-A). At this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence. - |
Uncertain significance, criteria provided, single submitter | clinical testing | Invitae | Aug 09, 2022 | This sequence change replaces glutamic acid, which is acidic and polar, with lysine, which is basic and polar, at codon 1118 of the RYR1 protein (p.Glu1118Lys). This variant is present in population databases (rs578234912, gnomAD 0.02%). This variant has not been reported in the literature in individuals affected with RYR1-related conditions. ClinVar contains an entry for this variant (Variation ID: 574610). 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 not expected to disrupt RYR1 protein function. 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. - |
not provided Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | GeneDx | Oct 24, 2022 | In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Has not been previously published as pathogenic or benign to our knowledge - |
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 | Aug 23, 2021 | - - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at