chr19-38473617-C-A
Variant summary
Our verdict is Uncertain significance. Variant got 1 ACMG points: 1P and 0B. PP2
The NM_000540.3(RYR1):c.4006C>A(p.Arg1336Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000446 in 1,568,190 control chromosomes in the GnomAD database, with no homozygous occurrence. 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. R1336L) 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 1 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
RYR1 | NM_000540.3 | c.4006C>A | p.Arg1336Ser | missense_variant | 28/106 | ENST00000359596.8 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
RYR1 | ENST00000359596.8 | c.4006C>A | p.Arg1336Ser | missense_variant | 28/106 | 5 | NM_000540.3 | A2 | |
RYR1 | ENST00000355481.8 | c.4006C>A | p.Arg1336Ser | missense_variant | 28/105 | 1 | P4 | ||
RYR1 | ENST00000599547.6 | c.4006C>A | p.Arg1336Ser | missense_variant, NMD_transcript_variant | 28/80 | 2 |
Frequencies
GnomAD3 genomes AF: 0.00000657 AC: 1AN: 152112Hom.: 0 Cov.: 31
GnomAD4 exome AF: 0.00000424 AC: 6AN: 1416078Hom.: 0 Cov.: 33 AF XY: 0.00000428 AC XY: 3AN XY: 700344
GnomAD4 genome AF: 0.00000657 AC: 1AN: 152112Hom.: 0 Cov.: 31 AF XY: 0.00 AC XY: 0AN XY: 74286
ClinVar
Submissions by phenotype
RYR1-related disorder Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Invitae | Oct 15, 2021 | This sequence change replaces arginine with serine at codon 1336 of the RYR1 protein (p.Arg1336Ser). The arginine residue is moderately conserved and there is a moderate physicochemical difference between arginine and serine. The frequency data for this variant in the population databases is considered unreliable, as metrics indicate poor data quality at this position in the ExAC database. This variant has not been reported in the literature in individuals with RYR1-related conditions. ClinVar contains an entry for this variant (Variation ID: 496649). 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 not expected to disrupt RYR1 protein function. Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may create or strengthen a splice site, but this prediction has not been confirmed by published transcriptional studies. 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. - |
Malignant hyperthermia of anesthesia Uncertain:1
Uncertain significance, criteria provided, single submitter | research | CSER _CC_NCGL, University of Washington | Oct 01, 2016 | Found in patient having exome sequencing for an unrelated indication. No known history of malignant hyperthermia. This interpretation considers GERP score and allele frequency data, in addition to published reports of the variant in the literature, available at the time of review. - |
not provided Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Revvity Omics, Revvity | May 07, 2019 | - - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at