rs751482960
Variant summary
Our verdict is Uncertain significance. Variant got 3 ACMG points: 3P and 0B. PP2PP3_Moderate
The NM_000540.3(RYR1):c.7640C>T(p.Ala2547Val) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000497 in 1,609,104 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 (★★). Synonymous variant affecting the same amino acid position (i.e. A2547A) has been classified as Likely benign.
Frequency
Consequence
NM_000540.3 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Uncertain_significance. Variant got 3 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
RYR1 | NM_000540.3 | c.7640C>T | p.Ala2547Val | missense_variant | 48/106 | ENST00000359596.8 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
RYR1 | ENST00000359596.8 | c.7640C>T | p.Ala2547Val | missense_variant | 48/106 | 5 | NM_000540.3 | A2 | |
RYR1 | ENST00000355481.8 | c.7640C>T | p.Ala2547Val | missense_variant | 48/105 | 1 | P4 | ||
RYR1 | ENST00000594335.5 | c.1094C>T | p.Ala365Val | missense_variant, NMD_transcript_variant | 9/49 | 1 | |||
RYR1 | ENST00000599547.6 | c.7640C>T | p.Ala2547Val | missense_variant, NMD_transcript_variant | 48/80 | 2 |
Frequencies
GnomAD3 genomes ? AF: 0.00000658 AC: 1AN: 152056Hom.: 0 Cov.: 29
GnomAD3 exomes AF: 0.00000405 AC: 1AN: 247082Hom.: 0 AF XY: 0.00000746 AC XY: 1AN XY: 134042
GnomAD4 exome AF: 0.00000480 AC: 7AN: 1457048Hom.: 0 Cov.: 36 AF XY: 0.00000414 AC XY: 3AN XY: 724912
GnomAD4 genome ? AF: 0.00000658 AC: 1AN: 152056Hom.: 0 Cov.: 29 AF XY: 0.0000135 AC XY: 1AN XY: 74262
ClinVar
Submissions by phenotype
Congenital multicore myopathy with external ophthalmoplegia Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Illumina Laboratory Services, Illumina | Jan 12, 2018 | This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score, this variant could not be ruled out of causing disease and therefore its association with disease required further investigation. A literature search was performed for the gene, cDNA change, and amino acid change (if applicable). No publications were found based on this search. This variant was therefore classified as a variant of unknown significance for this disease. - |
Central core myopathy Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Illumina Laboratory Services, Illumina | Jun 14, 2016 | - - |
Malignant hyperthermia, susceptibility to, 1 Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Illumina Laboratory Services, Illumina | Jan 12, 2018 | This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score, this variant could not be ruled out of causing disease and therefore its association with disease required further investigation. A literature search was performed for the gene, cDNA change, and amino acid change (if applicable). No publications were found based on this search. This variant was therefore classified as a variant of unknown significance for this disease. - |
RYR1-related disorder Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Invitae | Sep 27, 2022 | This sequence change replaces alanine, which is neutral and non-polar, with valine, which is neutral and non-polar, at codon 2547 of the RYR1 protein (p.Ala2547Val). The frequency data for this variant in the population databases is considered unreliable, as metrics indicate poor data quality at this position in the gnomAD database. This variant has not been reported in the literature in individuals affected with RYR1-related conditions. ClinVar contains an entry for this variant (Variation ID: 329065). 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. - |
Neuromuscular disease, congenital, with uniform type 1 fiber Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Illumina Laboratory Services, Illumina | Jun 14, 2016 | - - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at