rs766150328
Variant summary
Our verdict is Uncertain significance. Variant got 5 ACMG points: 5P and 0B. PM1PP2PP3_Moderate
The NM_000540.3(RYR1):c.1931G>A(p.Arg644His) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000174 in 1,613,200 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. R644C) has been classified as Uncertain significance.
Frequency
Consequence
NM_000540.3 missense
Scores
Clinical Significance
Conservation
Genome browser will be placed here
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.1931G>A | p.Arg644His | missense_variant | 18/106 | ENST00000359596.8 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
RYR1 | ENST00000359596.8 | c.1931G>A | p.Arg644His | missense_variant | 18/106 | 5 | NM_000540.3 | A2 | |
RYR1 | ENST00000355481.8 | c.1931G>A | p.Arg644His | missense_variant | 18/105 | 1 | P4 | ||
RYR1 | ENST00000599547.6 | c.1931G>A | p.Arg644His | missense_variant, NMD_transcript_variant | 18/80 | 2 |
Frequencies
GnomAD3 genomes ? AF: 0.00000658 AC: 1AN: 151904Hom.: 0 Cov.: 31
GnomAD3 exomes AF: 0.0000519 AC: 13AN: 250488Hom.: 0 AF XY: 0.0000591 AC XY: 8AN XY: 135396
GnomAD4 exome AF: 0.0000185 AC: 27AN: 1461296Hom.: 0 Cov.: 32 AF XY: 0.0000220 AC XY: 16AN XY: 726898
GnomAD4 genome ? AF: 0.00000658 AC: 1AN: 151904Hom.: 0 Cov.: 31 AF XY: 0.00 AC XY: 0AN XY: 74180
ClinVar
Submissions by phenotype
not provided Uncertain:2
Uncertain significance, criteria provided, single submitter | clinical testing | Eurofins Ntd Llc (ga) | Jul 11, 2014 | - - |
Uncertain significance, criteria provided, single submitter | clinical testing | CeGaT Center for Human Genetics Tuebingen | Mar 01, 2019 | - - |
RYR1-Related Disorders Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Invitae | Aug 16, 2022 | This sequence change replaces arginine, which is basic and polar, with histidine, which is basic and polar, at codon 644 of the RYR1 protein (p.Arg644His). This variant is present in population databases (rs766150328, gnomAD 0.009%). 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: 194814). 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. - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at