rs118192120
Variant summary
Our verdict is Uncertain significance. Variant got 3 ACMG points: 3P and 0B. PP2PP3_Moderate
The NM_000540.3(RYR1):c.4729G>A(p.Ala1577Thr) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000167 in 1,559,896 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. A1577A) 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.4729G>A | p.Ala1577Thr | missense_variant | 33/106 | ENST00000359596.8 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
RYR1 | ENST00000359596.8 | c.4729G>A | p.Ala1577Thr | missense_variant | 33/106 | 5 | NM_000540.3 | A2 | |
RYR1 | ENST00000355481.8 | c.4729G>A | p.Ala1577Thr | missense_variant | 33/105 | 1 | P4 | ||
RYR1 | ENST00000599547.6 | c.4729G>A | p.Ala1577Thr | missense_variant, NMD_transcript_variant | 33/80 | 2 |
Frequencies
GnomAD3 genomes AF: 0.0000394 AC: 6AN: 152160Hom.: 0 Cov.: 32
GnomAD3 exomes AF: 0.0000120 AC: 2AN: 166898Hom.: 0 AF XY: 0.00 AC XY: 0AN XY: 88482
GnomAD4 exome AF: 0.0000142 AC: 20AN: 1407618Hom.: 0 Cov.: 32 AF XY: 0.0000158 AC XY: 11AN XY: 695314
GnomAD4 genome AF: 0.0000394 AC: 6AN: 152278Hom.: 0 Cov.: 32 AF XY: 0.0000672 AC XY: 5AN XY: 74458
ClinVar
Submissions by phenotype
not provided Uncertain:2Other:1
Uncertain significance, criteria provided, single submitter | clinical testing | GeneDx | Feb 15, 2021 | Not observed at a significant frequency in large population cohorts (Lek et al., 2016); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Observed with a benign variant on the opposite allele (in trans) in a patient with congenital core myopathy in published published literature (Zhou et al., 2006); This variant is associated with the following publications: (PMID: 20301565, 17365175, 16940308) - |
Uncertain significance, criteria provided, single submitter | clinical testing | PreventionGenetics, part of Exact Sciences | Feb 21, 2017 | - - |
not provided, no classification provided | literature only | Leiden Muscular Dystrophy (RYR1) | - | - - |
Central core myopathy Pathogenic:1
Pathogenic, no assertion criteria provided | curation | GeneReviews | May 11, 2010 | - - |
RYR1-related disorder Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Invitae | Aug 23, 2022 | This sequence change replaces alanine, which is neutral and non-polar, with threonine, which is neutral and polar, at codon 1577 of the RYR1 protein (p.Ala1577Thr). The frequency data for this variant in the population databases is considered unreliable, as metrics indicate poor data quality at this position in the gnomAD database. This missense change has been observed in individual(s) with congenital myopathy (PMID: 16940308). ClinVar contains an entry for this variant (Variation ID: 65923). 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 expected to disrupt RYR1 protein function. Experimental studies have shown that this missense change does not substantially affect RYR1 function (PMID: 16940308). 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. - |
Malignant hyperthermia, susceptibility to, 1 Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | All of Us Research Program, National Institutes of Health | Nov 30, 2023 | This missense variant replaces alanine with threonine at codon 1577 of the RYR1 protein. Computational prediction suggests that this variant may have deleterious impact on protein structure and function (internally defined REVEL score threshold >= 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 autosomal dominant malignant hyperthermia in the literature, although it is associated with other phenotype(s) (ClinVar variation ID: 65923). This variant has been identified in 3/198252 chromosomes in the general population by the Genome Aggregation Database (gnomAD). Due to insufficient evidence, this variant is classified as a Variant of Uncertain Significance for autosomal dominant malignant hyperthermia. - |
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 | Apr 01, 2022 | - - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at