rs758210285
Variant summary
Our verdict is Uncertain significance. Variant got 4 ACMG points: 4P and 0B. PP2PP3_ModeratePP5
The NM_000540.3(RYR1):c.9623C>T(p.Pro3208Leu) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000771 in 1,556,552 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 Conflicting classifications of pathogenicity (no stars).
Frequency
Consequence
NM_000540.3 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Uncertain_significance. Variant got 4 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | Protein | UniProt |
---|---|---|---|---|---|---|---|---|
RYR1 | NM_000540.3 | c.9623C>T | p.Pro3208Leu | missense_variant | 65/106 | ENST00000359596.8 | NP_000531.2 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Protein | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|---|
RYR1 | ENST00000359596.8 | c.9623C>T | p.Pro3208Leu | missense_variant | 65/106 | 5 | NM_000540.3 | ENSP00000352608 | A2 | |
RYR1 | ENST00000355481.8 | c.9623C>T | p.Pro3208Leu | missense_variant | 65/105 | 1 | ENSP00000347667 | P4 | ||
RYR1 | ENST00000594335.5 | c.*366C>T | 3_prime_UTR_variant, NMD_transcript_variant | 25/49 | 1 | ENSP00000470927 | ||||
RYR1 | ENST00000599547.6 | c.*382C>T | 3_prime_UTR_variant, NMD_transcript_variant | 64/80 | 2 | ENSP00000471601 |
Frequencies
GnomAD3 genomes AF: 0.00000657 AC: 1AN: 152202Hom.: 0 Cov.: 32
GnomAD4 exome AF: 0.00000783 AC: 11AN: 1404350Hom.: 0 Cov.: 31 AF XY: 0.0000130 AC XY: 9AN XY: 693132
GnomAD4 genome AF: 0.00000657 AC: 1AN: 152202Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0AN XY: 74360
ClinVar
Submissions by phenotype
RYR1-related disorder Pathogenic:2
Likely pathogenic, no assertion criteria provided | clinical testing | PreventionGenetics, part of Exact Sciences | Oct 19, 2023 | The RYR1 c.9623C>T variant is predicted to result in the amino acid substitution p.Pro3208Leu. This variant has been reported in the compound heterozygous state in two patients affected with congenital myopathy (Kalfon et al. 2022. PubMed ID: 34970863; Chang et al. 2022. PubMed ID: 35693006). Additionally, we have observed this variant alongside a second plausible causative variant in the RYR1 gene in other patients at PreventionGenetics affected with congenital myopathy. This variant is reported in 0.0052% of alleles in individuals of European (Finnish) descent in gnomAD (http://gnomad.broadinstitute.org/variant/19-39006795-C-T). This variant is interpreted as likely pathogenic. - |
Pathogenic, criteria provided, single submitter | clinical testing | Labcorp Genetics (formerly Invitae), Labcorp | Jan 16, 2024 | This sequence change replaces proline, which is neutral and non-polar, with leucine, which is neutral and non-polar, at codon 3208 of the RYR1 protein (p.Pro3208Leu). This variant is present in population databases (rs758210285, gnomAD 0.005%). This missense change has been observed in individual(s) with clinical features of autosomal recessive RYR1-related myopathy (Invitae). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. ClinVar contains an entry for this variant (Variation ID: 586415). 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 with a positive predictive value of 95%. For these reasons, this variant has been classified as Pathogenic. - |
not provided Pathogenic:1Uncertain:1
Likely pathogenic, criteria provided, single submitter | clinical testing | GeneDx | Feb 27, 2024 | Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 34970863, 35693006, 12668474) - |
Uncertain significance, criteria provided, single submitter | clinical testing | Athena Diagnostics | Jun 05, 2018 | - - |
RYR1-related myopathy Pathogenic:1
Likely pathogenic, criteria provided, single submitter | provider interpretation | Pediatric Department, Peking University First Hospital | Feb 08, 2022 | - - |
Malignant hyperthermia, susceptibility to, 1 Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | All of Us Research Program, National Institutes of Health | Sep 05, 2023 | - - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at