rs193922883
Variant summary
Our verdict is Pathogenic. Variant got 11 ACMG points: 11P and 0B. PM1PM2PM5PP2PP3_Strong
The NM_000540.3(RYR1):c.14639T>A(p.Met4880Lys) 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. M4880T) 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.14639T>A | p.Met4880Lys | missense_variant | 101/106 | ENST00000359596.8 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
RYR1 | ENST00000359596.8 | c.14639T>A | p.Met4880Lys | missense_variant | 101/106 | 5 | NM_000540.3 | A2 |
Frequencies
GnomAD3 genomes ? Cov.: 31
GnomAD4 exome Cov.: 34
GnomAD4 genome ? Cov.: 31
ClinVar
Submissions by phenotype
RYR1-related disorder Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Invitae | Aug 01, 2019 | 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. This missense change is located in a region of the RYR1 protein where a significant number of previously reported RYR1 missense mutations are found (PMID: 16084090). These observations suggest that a previously unreported missense substitution within this region may affect protein function, but experiments have not been done to test this possibility. Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Benign"; Align-GVGD: "Class C0"). This variant has not been reported in the literature in individuals with RYR1-related conditions. ClinVar contains an entry for this variant (Variation ID: 285088). This variant is not present in population databases (ExAC no frequency). This sequence change replaces methionine with lysine at codon 4880 of the RYR1 protein (p.Met4880Lys). The methionine residue is highly conserved and there is a moderate physicochemical difference between methionine and lysine. - |
not provided Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Eurofins Ntd Llc (ga) | Dec 28, 2015 | - - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at