rs754431075
Variant summary
Our verdict is Uncertain significance. Variant got 1 ACMG points: 1P and 0B. PP2
The NM_000540.3(RYR1):c.9772G>A(p.Glu3258Lys) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000378 in 1,614,074 control chromosomes in the GnomAD database, with no homozygous occurrence. 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. E3258Q) 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 1 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
RYR1 | NM_000540.3 | c.9772G>A | p.Glu3258Lys | missense_variant | 66/106 | ENST00000359596.8 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
RYR1 | ENST00000359596.8 | c.9772G>A | p.Glu3258Lys | missense_variant | 66/106 | 5 | NM_000540.3 | A2 | |
RYR1 | ENST00000355481.8 | c.9772G>A | p.Glu3258Lys | missense_variant | 66/105 | 1 | P4 | ||
RYR1 | ENST00000594335.5 | c.*515G>A | 3_prime_UTR_variant, NMD_transcript_variant | 26/49 | 1 | ||||
RYR1 | ENST00000599547.6 | c.*531G>A | 3_prime_UTR_variant, NMD_transcript_variant | 65/80 | 2 |
Frequencies
GnomAD3 genomes AF: 0.0000658 AC: 10AN: 152086Hom.: 0 Cov.: 31
GnomAD3 exomes AF: 0.0000760 AC: 19AN: 249908Hom.: 0 AF XY: 0.0000591 AC XY: 8AN XY: 135282
GnomAD4 exome AF: 0.0000349 AC: 51AN: 1461870Hom.: 0 Cov.: 34 AF XY: 0.0000358 AC XY: 26AN XY: 727238
GnomAD4 genome AF: 0.0000657 AC: 10AN: 152204Hom.: 0 Cov.: 31 AF XY: 0.0000806 AC XY: 6AN XY: 74426
ClinVar
Submissions by phenotype
not provided Uncertain:2
Uncertain significance, criteria provided, single submitter | clinical testing | GeneDx | Dec 05, 2019 | In silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect; Has not been previously published as pathogenic or benign to our knowledge - |
Uncertain significance, criteria provided, single submitter | clinical testing | Revvity Omics, Revvity | Jun 28, 2023 | - - |
RYR1-related disorder Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Invitae | Jan 25, 2024 | This sequence change replaces glutamic acid, which is acidic and polar, with lysine, which is basic and polar, at codon 3258 of the RYR1 protein (p.Glu3258Lys). This variant is present in population databases (rs754431075, gnomAD 0.04%). 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: 568062). 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) has been performed at Invitae for this missense variant, however the output from this modeling did not meet the statistical confidence thresholds required to predict the impact of this variant on 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. - |
RYR1-related myopathy Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Molecular Genetics, Royal Melbourne Hospital | Mar 30, 2023 | This sequence change in RYR1 is predicted to replace glutamic acid with lysine at codon 3258, p.(Glu3258Lys). The glutamic acid residue is highly conserved (100 vertebrates, UCSC), and is located in exon 66 outside of the C-terminal region, amino acids 4631-4991, that is defined as a mutational hotspot. There is a small physicochemical difference between glutamic acid and lysine. The highest population minor allele frequency in gnomAD v2.1 is 0.03% (12/3,4584 alleles, 0 homozygotes) in the Latino/admixed American population. The variant has been reported as a variant of uncertain significance (ClinVar ID: 568062), and to our knowledge, has not been reported in the literature in any individuals with RYR1-related disorders. Multiple lines of computational evidence predict a deleterious effect for the missense substitution (5/5 algorithms). Based on the classification scheme RMH Modified ACMG Guidelines v1.4.0, this variant is classified as a VARIANT OF UNCERTAIN SIGNIFICANCE. Following criteria are met: PP3. - |
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 | Sep 01, 2021 | - - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at