NM_000540.3:c.821G>C
Variant summary
Our verdict is Uncertain significance. Variant got 3 ACMG points: 3P and 0B. PM1PP2
The NM_000540.3(RYR1):c.821G>C(p.Arg274Pro) variant causes a missense change. The variant allele was found at a frequency of 0.0000236 in 1,610,012 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. R274H) 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 3 ACMG points.
Transcripts
RefSeq
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | Exon rank | TSL | MANE | Protein | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|---|
RYR1 | ENST00000359596.8 | c.821G>C | p.Arg274Pro | missense_variant | Exon 10 of 106 | 5 | NM_000540.3 | ENSP00000352608.2 | ||
RYR1 | ENST00000355481.8 | c.821G>C | p.Arg274Pro | missense_variant | Exon 10 of 105 | 1 | ENSP00000347667.3 | |||
RYR1 | ENST00000599547.6 | n.821G>C | non_coding_transcript_exon_variant | Exon 10 of 80 | 2 | ENSP00000471601.2 |
Frequencies
GnomAD3 genomes AF: 0.000118 AC: 18AN: 152160Hom.: 0 Cov.: 31
GnomAD3 exomes AF: 0.0000445 AC: 11AN: 247018Hom.: 0 AF XY: 0.0000447 AC XY: 6AN XY: 134134
GnomAD4 exome AF: 0.0000137 AC: 20AN: 1457852Hom.: 0 Cov.: 31 AF XY: 0.0000124 AC XY: 9AN XY: 725408
GnomAD4 genome AF: 0.000118 AC: 18AN: 152160Hom.: 0 Cov.: 31 AF XY: 0.0000807 AC XY: 6AN XY: 74338
ClinVar
Submissions by phenotype
not provided Uncertain:3
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RYR1-related disorder Uncertain:1
This sequence change replaces arginine, which is basic and polar, with proline, which is neutral and non-polar, at codon 274 of the RYR1 protein (p.Arg274Pro). This variant is present in population databases (rs368711923, gnomAD 0.05%). This missense change has been observed in individual(s) with clinical features of RYR1-related conditions (Invitae). ClinVar contains an entry for this variant (Variation ID: 544424). 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 with a negative predictive value of 95%. 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
This missense variant replaces arginine with proline at codon 274 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 12/278392 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. -
Central core myopathy Uncertain:1
This variant was determined to be of uncertain significance according to ACMG Guidelines, 2015 [PMID:25741868]. -
Congenital myopathy with fiber type disproportion;C1840365:King Denborough syndrome;C1850674:Congenital multicore myopathy with external ophthalmoplegia;C2930980:Malignant hyperthermia, susceptibility to, 1;C5830701:Central core myopathy Uncertain:1
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Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at