rs587784371
Variant summary
Our verdict is Uncertain significance. Variant got 5 ACMG points: 5P and 0B. PM1PP2PP3_Moderate
The NM_000540.3(RYR1):c.1001G>A(p.Gly334Asp) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000479 in 1,461,878 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 (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. G334V) 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.1001G>A | p.Gly334Asp | missense_variant | 11/106 | ENST00000359596.8 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
RYR1 | ENST00000359596.8 | c.1001G>A | p.Gly334Asp | missense_variant | 11/106 | 5 | NM_000540.3 | A2 | |
RYR1 | ENST00000355481.8 | c.1001G>A | p.Gly334Asp | missense_variant | 11/105 | 1 | P4 | ||
RYR1 | ENST00000599547.6 | c.1001G>A | p.Gly334Asp | missense_variant, NMD_transcript_variant | 11/80 | 2 |
Frequencies
GnomAD3 genomes ? Cov.: 31
GnomAD3 exomes AF: 0.0000159 AC: 4AN: 251406Hom.: 0 AF XY: 0.00000736 AC XY: 1AN XY: 135896
GnomAD4 exome AF: 0.00000479 AC: 7AN: 1461878Hom.: 0 Cov.: 31 AF XY: 0.00000275 AC XY: 2AN XY: 727244
GnomAD4 genome ? Cov.: 31
ClinVar
Submissions by phenotype
RYR1-related disorder Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Invitae | Jun 10, 2022 | This sequence change replaces glycine, which is neutral and non-polar, with aspartic acid, which is acidic and polar, at codon 334 of the RYR1 protein (p.Gly334Asp). This variant is present in population databases (rs587784371, gnomAD 0.006%). This variant has not been reported in the literature in individuals affected with RYR1-related conditions. 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. - |
not provided Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | CeGaT Center for Human Genetics Tuebingen | Oct 01, 2022 | RYR1: PM2 - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at