chr19-38440823-G-C
Variant summary
Our verdict is Likely pathogenic. Variant got 9 ACMG points: 9P and 0B. PM1PM2PP2PP3_Strong
The NM_000540.3(RYR1):c.124G>C(p.Gly42Arg) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000206 in 1,457,848 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. G42D) has been classified as Uncertain significance.
Frequency
Consequence
NM_000540.3 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Likely_pathogenic. Variant got 9 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
RYR1 | NM_000540.3 | c.124G>C | p.Gly42Arg | missense_variant | 2/106 | ENST00000359596.8 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
RYR1 | ENST00000359596.8 | c.124G>C | p.Gly42Arg | missense_variant | 2/106 | 5 | NM_000540.3 | A2 | |
RYR1 | ENST00000355481.8 | c.124G>C | p.Gly42Arg | missense_variant | 2/105 | 1 | P4 | ||
RYR1 | ENST00000599547.6 | c.124G>C | p.Gly42Arg | missense_variant, NMD_transcript_variant | 2/80 | 2 |
Frequencies
GnomAD3 genomes ? Cov.: 32
GnomAD4 exome AF: 0.00000206 AC: 3AN: 1457848Hom.: 0 Cov.: 31 AF XY: 0.00000276 AC XY: 2AN XY: 725066
GnomAD4 genome ? Cov.: 32
ClinVar
Submissions by phenotype
Inborn genetic diseases Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Ambry Genetics | Dec 06, 2016 | - - |
RYR1-related disorder Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Invitae | Oct 03, 2021 | 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. 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. ClinVar contains an entry for this variant (Variation ID: 521422). This variant has not been reported in the literature in individuals affected with RYR1-related conditions. This variant is not present in population databases (ExAC no frequency). This sequence change replaces glycine with arginine at codon 42 of the RYR1 protein (p.Gly42Arg). The glycine residue is moderately conserved and there is a moderate physicochemical difference between glycine and arginine. - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at