rs201545585
Variant summary
Our verdict is Uncertain significance. Variant got 3 ACMG points: 3P and 0B. PM2PP2
The NM_000540.3(RYR1):c.2533C>T(p.Leu845Phe) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000248 in 1,613,802 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. L845I) 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 3 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
RYR1 | NM_000540.3 | c.2533C>T | p.Leu845Phe | missense_variant | 20/106 | ENST00000359596.8 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
RYR1 | ENST00000359596.8 | c.2533C>T | p.Leu845Phe | missense_variant | 20/106 | 5 | NM_000540.3 | A2 | |
RYR1 | ENST00000355481.8 | c.2533C>T | p.Leu845Phe | missense_variant | 20/105 | 1 | P4 | ||
RYR1 | ENST00000599547.6 | c.2533C>T | p.Leu845Phe | missense_variant, NMD_transcript_variant | 20/80 | 2 |
Frequencies
GnomAD3 genomes ? AF: 0.00000657 AC: 1AN: 152272Hom.: 0 Cov.: 33
GnomAD3 exomes AF: 0.00000398 AC: 1AN: 251042Hom.: 0 AF XY: 0.00 AC XY: 0AN XY: 135746
GnomAD4 exome AF: 0.00000205 AC: 3AN: 1461530Hom.: 0 Cov.: 32 AF XY: 0.00000413 AC XY: 3AN XY: 727080
GnomAD4 genome ? AF: 0.00000657 AC: 1AN: 152272Hom.: 0 Cov.: 33 AF XY: 0.00 AC XY: 0AN XY: 74394
ClinVar
Submissions by phenotype
Malignant hyperthermia, susceptibility to, 1 Uncertain:1
Uncertain significance, criteria provided, single submitter | research | Biesecker Lab/Clinical Genomics Section, National Institutes of Health | Jul 01, 2013 | - - |
RYR1-Related Disorders Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Invitae | May 24, 2022 | This sequence change replaces leucine, which is neutral and non-polar, with phenylalanine, which is neutral and non-polar, at codon 845 of the RYR1 protein (p.Leu845Phe). This variant is present in population databases (rs201545585, gnomAD 0.007%). 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: 224374). 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. - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at