19-38463490-C-T
Variant summary
Our verdict is Uncertain significance. Variant got 2 ACMG points: 2P and 0B. PP2PP3
The NM_000540.3(RYR1):c.2645C>T(p.Ala882Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00035 in 1,613,228 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★). Synonymous variant affecting the same amino acid position (i.e. A882A) has been classified as Likely benign.
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.2645C>T | p.Ala882Val | missense_variant | 21/106 | ENST00000359596.8 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
RYR1 | ENST00000359596.8 | c.2645C>T | p.Ala882Val | missense_variant | 21/106 | 5 | NM_000540.3 | A2 | |
RYR1 | ENST00000355481.8 | c.2645C>T | p.Ala882Val | missense_variant | 21/105 | 1 | P4 | ||
RYR1 | ENST00000599547.6 | c.2645C>T | p.Ala882Val | missense_variant, NMD_transcript_variant | 21/80 | 2 |
Frequencies
GnomAD3 genomes ? AF: 0.000217 AC: 33AN: 152136Hom.: 0 Cov.: 30
GnomAD3 exomes AF: 0.000144 AC: 36AN: 250022Hom.: 0 AF XY: 0.000111 AC XY: 15AN XY: 135320
GnomAD4 exome AF: 0.000363 AC: 531AN: 1461092Hom.: 0 Cov.: 33 AF XY: 0.000338 AC XY: 246AN XY: 726910
GnomAD4 genome ? AF: 0.000217 AC: 33AN: 152136Hom.: 0 Cov.: 30 AF XY: 0.000188 AC XY: 14AN XY: 74316
ClinVar
Submissions by phenotype
Malignant hyperthermia, susceptibility to, 1 Uncertain:2
Uncertain significance, criteria provided, single submitter | clinical testing | All of Us Research Program, National Institutes of Health | Feb 05, 2024 | This missense variant replaces alanine with valine at codon 882 of the RYR1 protein. Computational prediction is inconclusive regarding the impact of this variant on protein structure and function (internally defined REVEL score threshold 0.5 < inconclusive < 0.7, PMID: 27666373). To our knowledge, functional studies have not been reported for this variant. This variant has not been reported in individuals affected with RYR1-related disorders in the literature. This variant has been identified in 41/281414 chromosomes in the general population by the Genome Aggregation Database (gnomAD). The available evidence is insufficient to determine the role of this variant in disease conclusively. Therefore, this variant is classified as a Variant of Uncertain Significance. - |
Uncertain significance, criteria provided, single submitter | clinical testing | Illumina Laboratory Services, Illumina | Jan 13, 2018 | This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score, this variant could not be ruled out of causing disease and therefore its association with disease required further investigation. A literature search was performed for the gene, cDNA change, and amino acid change (if applicable). No publications were found based on this search. This variant was therefore classified as a variant of unknown significance for this disease. - |
Congenital multicore myopathy with external ophthalmoplegia Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Illumina Laboratory Services, Illumina | Jan 13, 2018 | This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score, this variant could not be ruled out of causing disease and therefore its association with disease required further investigation. A literature search was performed for the gene, cDNA change, and amino acid change (if applicable). No publications were found based on this search. This variant was therefore classified as a variant of unknown significance for this disease. - |
Central core myopathy Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Baylor Genetics | Nov 27, 2018 | This variant was determined to be of uncertain significance according to ACMG Guidelines, 2015 [PMID:25741868]. - |
RYR1-related disorder Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Invitae | Jan 26, 2024 | This sequence change replaces alanine, which is neutral and non-polar, with valine, which is neutral and non-polar, at codon 882 of the RYR1 protein (p.Ala882Val). This variant is present in population databases (rs143701391, gnomAD 0.03%). This missense change has been observed in individual(s) with a suspected mitochondrial disorder (PMID: 24215330). ClinVar contains an entry for this variant (Variation ID: 201145). 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. - |
not provided Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Revvity Omics, Revvity | Sep 20, 2022 | - - |
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 20, 2021 | - - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at