rs780420237
Variant summary
Our verdict is Uncertain significance. Variant got 5 ACMG points: 5P and 0B. PM2PP2PP3_Moderate
The NM_000540.3(RYR1):āc.4766A>Cā(p.Gln1589Pro) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000128 in 1,561,364 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 (ā ā ). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. Q1589K) has been classified as Uncertain significance.
Frequency
Consequence
NM_000540.3 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Uncertain_significance. Variant got 5 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
RYR1 | NM_000540.3 | c.4766A>C | p.Gln1589Pro | missense_variant | 33/106 | ENST00000359596.8 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
RYR1 | ENST00000359596.8 | c.4766A>C | p.Gln1589Pro | missense_variant | 33/106 | 5 | NM_000540.3 | A2 | |
RYR1 | ENST00000355481.8 | c.4766A>C | p.Gln1589Pro | missense_variant | 33/105 | 1 | P4 | ||
RYR1 | ENST00000599547.6 | c.4766A>C | p.Gln1589Pro | missense_variant, NMD_transcript_variant | 33/80 | 2 |
Frequencies
GnomAD3 genomes AF: 0.00000657 AC: 1AN: 152158Hom.: 0 Cov.: 31
GnomAD3 exomes AF: 0.00000590 AC: 1AN: 169454Hom.: 0 AF XY: 0.00 AC XY: 0AN XY: 89940
GnomAD4 exome AF: 7.10e-7 AC: 1AN: 1409206Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0AN XY: 696100
GnomAD4 genome AF: 0.00000657 AC: 1AN: 152158Hom.: 0 Cov.: 31 AF XY: 0.00 AC XY: 0AN XY: 74334
ClinVar
Submissions by phenotype
RYR1-related disorder Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Invitae | Jul 24, 2022 | This sequence change replaces glutamine, which is neutral and polar, with proline, which is neutral and non-polar, at codon 1589 of the RYR1 protein (p.Gln1589Pro). This variant is present in population databases (rs780420237, gnomAD 0.002%). 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: 544377). 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. 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. - |
RYR1-related myopathy Uncertain:1
Uncertain significance, criteria provided, single submitter | curation | Broad Center for Mendelian Genomics, Broad Institute of MIT and Harvard | Jan 25, 2023 | The heterozygous p.Gln1589Pro variant in RYR1 was identified by our study, in the compound heterozygous state with a variant of uncertain significance (NC_000019.10:g.38587339G>T), in one individual with central core disease. Familial segregation analysis revealed that this variant was in trans with another variant of uncertain significance (NC_000019.10:g.38587339G>T). The p.Gln1589Pro variant in RYR1 has not been previously reported in the literature in individuals with RYR1-related myopathy but has been identified in 0.001% (1/68664) of European (non-Finnish) chromosomes by the Genome Aggregation Database (gnomAD, http://gnomad.broadinstitute.org; dbSNP ID: rs780420237). Although this variant has been seen in the general population in a heterozygous state, its frequency is low enough to be consistent with a recessive carrier frequency. This variant has also been reported in ClinVar (Variation ID: 544377) and has been interpreted as a variant of uncertain significance by Invitae and Prevention Genetics. Computational prediction tools and conservation analyses suggest that this variant may impact the protein, though this information is not predictive enough to determine pathogenicity. In summary, the clinical significance of the p.Gln1589Pro variant is uncertain. ACMG/AMP Criteria applied: PM2_Supporting, PP3 (Richards 2015). - |
not provided Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | PreventionGenetics, part of Exact Sciences | Aug 26, 2016 | - - |
Congenital myopathy with fiber type disproportion;C0751951:Central core myopathy;C1840365:King Denborough syndrome;C1850674:Congenital multicore myopathy with external ophthalmoplegia;C2930980:Malignant hyperthermia, susceptibility to, 1 Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Fulgent Genetics, Fulgent Genetics | Sep 10, 2021 | - - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at