15-33473504-G-A
Variant summary
Our verdict is Likely pathogenic. Variant got 6 ACMG points: 6P and 0B. PM2PP3_Strong
The NM_001036.6(RYR3):c.137G>A(p.Arg46His) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000062 in 1,613,860 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 (★★).
Frequency
Consequence
NM_001036.6 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Likely_pathogenic. Variant got 6 ACMG points.
Transcripts
RefSeq
Ensembl
Frequencies
GnomAD3 genomes AF: 0.00000657 AC: 1AN: 152180Hom.: 0 Cov.: 32
GnomAD3 exomes AF: 0.0000201 AC: 5AN: 249248Hom.: 0 AF XY: 0.0000148 AC XY: 2AN XY: 135222
GnomAD4 exome AF: 0.00000616 AC: 9AN: 1461680Hom.: 0 Cov.: 32 AF XY: 0.00000413 AC XY: 3AN XY: 727122
GnomAD4 genome AF: 0.00000657 AC: 1AN: 152180Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0AN XY: 74338
ClinVar
Submissions by phenotype
not specified Uncertain:1
Variant summary: RYR3 c.137G>A (p.Arg46His) results in a non-conservative amino acid change located in the Inositol 1,4,5-trisphosphate/ryanodine receptor (IPR014821) of the encoded protein sequence. Four of four in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 2e-05 in 249248 control chromosomes. The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. To our knowledge, no occurrence of c.137G>A in individuals affected with Congenital Myopathy 20 and no experimental evidence demonstrating its impact on protein function have been reported. ClinVar contains an entry for this variant (Variation ID: 1395319). Based on the evidence outlined above, the variant was classified as uncertain significance. -
Epileptic encephalopathy Uncertain:1
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. 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: "Probably Damaging"; Align-GVGD: "Class C0"). This variant has not been reported in the literature in individuals with RYR3-related conditions. This variant is present in population databases (rs774050928, ExAC 0.009%). This sequence change replaces arginine with histidine at codon 46 of the RYR3 protein (p.Arg46His). The arginine residue is moderately conserved and there is a small physicochemical difference between arginine and histidine. -
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at