rs118192139
Variant summary
Our verdict is Pathogenic. Variant got 12 ACMG points: 12P and 0B. PM1PM2PM5PP2PP3_StrongPP5
The NM_000540.3(RYR1):c.13952A>C(p.His4651Pro) 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 Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. H4651R) has been classified as Likely pathogenic.
Frequency
Consequence
NM_000540.3 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Pathogenic. Variant got 12 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
RYR1 | NM_000540.3 | c.13952A>C | p.His4651Pro | missense_variant | 95/106 | ENST00000359596.8 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
RYR1 | ENST00000359596.8 | c.13952A>C | p.His4651Pro | missense_variant | 95/106 | 5 | NM_000540.3 | A2 |
Frequencies
GnomAD3 genomes ? Cov.: 32
GnomAD4 exome Cov.: 33
GnomAD4 genome ? Cov.: 32
ClinVar
Submissions by phenotype
Central core myopathy Pathogenic:2
Pathogenic, no assertion criteria provided | curation | GeneReviews | May 11, 2010 | - - |
Pathogenic, criteria provided, single submitter | clinical testing | Neuberg Centre For Genomic Medicine, NCGM | - | The missense variant p.H4651P in RYR1 (NM_000540.3) has been previously reported in one patient in heterozygous state. The father of the patient was detected to be somatic mosaic for the same variant ( Davis MR et al). The variant is present in the hot-spot region for central core disease. It has been submitted to ClinVar as Pathogenic. The p.H4651P variant is novel (not in any individuals) in gnomAD Exomes and is novel (not in any individuals) in 1000 Genomes. The p.H4651P missense variant is predicted to be damaging by both SIFT and PolyPhen2. The histidine residue at codon 4651 of RYR1 is conserved in all mammalian species. The nucleotide c.13952 in RYR1 is predicted conserved by GERP++ and PhyloP across 100 vertebrates. For these reasons, this variant has been classified as Pathogenic. - |
RYR1-related disorder Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Invitae | Dec 30, 2022 | 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. This variant disrupts the p.His4651 amino acid residue in RYR1. Other variant(s) that disrupt this residue have been observed in individuals with RYR1-related conditions (PMID: 12565913, 35428369), which suggests that this may be a clinically significant amino acid residue. 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. ClinVar contains an entry for this variant (Variation ID: 65951). This missense change has been observed in individual(s) with central core disease (PMID: 12565913). This variant is not present in population databases (gnomAD no frequency). This sequence change replaces histidine, which is basic and polar, with proline, which is neutral and non-polar, at codon 4651 of the RYR1 protein (p.His4651Pro). - |
not provided Other:1
not provided, no classification provided | literature only | Leiden Muscular Dystrophy (RYR1) | - | - - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at