rs764009626
Variant summary
Our verdict is Uncertain significance. Variant got 3 ACMG points: 3P and 0B. PM1PP2
The NM_000540.3(RYR1):c.3257G>A(p.Arg1086His) variant causes a missense change. The variant allele was found at a frequency of 0.0000291 in 1,614,250 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. R1086C) 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.3257G>A | p.Arg1086His | missense_variant | 25/106 | ENST00000359596.8 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
RYR1 | ENST00000359596.8 | c.3257G>A | p.Arg1086His | missense_variant | 25/106 | 5 | NM_000540.3 | A2 | |
RYR1 | ENST00000355481.8 | c.3257G>A | p.Arg1086His | missense_variant | 25/105 | 1 | P4 | ||
RYR1 | ENST00000594111.1 | n.350G>A | non_coding_transcript_exon_variant | 2/2 | 2 | ||||
RYR1 | ENST00000599547.6 | c.3257G>A | p.Arg1086His | missense_variant, NMD_transcript_variant | 25/80 | 2 |
Frequencies
GnomAD3 genomes AF: 0.0000131 AC: 2AN: 152256Hom.: 0 Cov.: 32
GnomAD3 exomes AF: 0.0000358 AC: 9AN: 251462Hom.: 0 AF XY: 0.0000441 AC XY: 6AN XY: 135910
GnomAD4 exome AF: 0.0000308 AC: 45AN: 1461876Hom.: 0 Cov.: 31 AF XY: 0.0000261 AC XY: 19AN XY: 727234
GnomAD4 genome AF: 0.0000131 AC: 2AN: 152374Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0AN XY: 74516
ClinVar
Submissions by phenotype
Malignant hyperthermia, susceptibility to, 1 Uncertain:2
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. - |
Uncertain significance, criteria provided, single submitter | clinical testing | All of Us Research Program, National Institutes of Health | Dec 18, 2023 | This missense variant replaces arginine with histidine at codon 1086 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 been reported in one family affected with malignant hyperthermia susceptibility and did not consistently segregate with disease (PMID: 33564012). This variant has been identified in 10/282866 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. - |
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. - |
RYR1-related disorder Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Invitae | Jul 12, 2022 | This sequence change replaces arginine, which is basic and polar, with histidine, which is basic and polar, at codon 1086 of the RYR1 protein (p.Arg1086His). This variant is present in population databases (rs764009626, gnomAD 0.006%). This missense change has been observed in individual(s) with clinical features of autosomal dominant congenital myopathy and/or malignant hyperthermia (PMID: 3356401; Invitae). ClinVar contains an entry for this variant (Variation ID: 572240). 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. - |
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 | Oct 11, 2021 | - - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at