19-38543365-G-C
Variant summary
Our verdict is Likely pathogenic. Variant got 9 ACMG points: 9P and 0B. PM2PM5PP2PP3_Strong
The NM_000540.3(RYR1):c.11708G>C(p.Arg3903Pro) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. 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. R3903Q) has been classified as Pathogenic.
Frequency
Consequence
NM_000540.3 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Likely_pathogenic. Variant got 9 ACMG points.
Transcripts
RefSeq
Ensembl
Frequencies
GnomAD3 genomes Cov.: 32
GnomAD4 exome Cov.: 32
GnomAD4 genome Cov.: 32
ClinVar
Submissions by phenotype
Malignant hyperthermia, susceptibility to, 1 Uncertain:1
This missense variant replaces arginine with proline at codon 3903 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 RYR1-related disorders in the literature. This variant has not been identified in the general population by the Genome Aggregation Database (gnomAD). A different missense variant occurring at the same codon, p.Arg3903Gln, is known to cause disease (ClinVar variation ID: 133017), indicating that arginine at this position is important for RYR1 protein function. Although there is a suspicion for a pathogenic role, the role of p.Arg3903Pro variant in disease cannot be determined conclusively due to the lack of data specific for the variant. Therefore, this variant is classified as a Variant of Uncertain Significance. -
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at
Publications
No publications associated with this variant yet.