19-38519384-G-A
Variant summary
Our verdict is Uncertain significance. Variant got 2 ACMG points: 2P and 0B. PP2PP3
The NM_000540.3(RYR1):c.10189G>A(p.Glu3397Lys) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000112 in 1,605,974 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. E3397Q) 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 2 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
RYR1 | NM_000540.3 | c.10189G>A | p.Glu3397Lys | missense_variant | 67/106 | ENST00000359596.8 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
RYR1 | ENST00000359596.8 | c.10189G>A | p.Glu3397Lys | missense_variant | 67/106 | 5 | NM_000540.3 | A2 | |
RYR1 | ENST00000355481.8 | c.10189G>A | p.Glu3397Lys | missense_variant | 67/105 | 1 | P4 | ||
RYR1 | ENST00000594335.5 | c.*932G>A | 3_prime_UTR_variant, NMD_transcript_variant | 27/49 | 1 | ||||
RYR1 | ENST00000599547.6 | c.*948G>A | 3_prime_UTR_variant, NMD_transcript_variant | 66/80 | 2 |
Frequencies
GnomAD3 genomes AF: 0.0000263 AC: 4AN: 152216Hom.: 0 Cov.: 32
GnomAD3 exomes AF: 0.0000343 AC: 8AN: 233288Hom.: 0 AF XY: 0.0000396 AC XY: 5AN XY: 126210
GnomAD4 exome AF: 0.00000963 AC: 14AN: 1453640Hom.: 0 Cov.: 32 AF XY: 0.00000969 AC XY: 7AN XY: 722646
GnomAD4 genome AF: 0.0000263 AC: 4AN: 152334Hom.: 0 Cov.: 32 AF XY: 0.0000403 AC XY: 3AN XY: 74502
ClinVar
Submissions by phenotype
Malignant hyperthermia, susceptibility to, 1 Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | All of Us Research Program, National Institutes of Health | Jan 08, 2024 | This missense variant replaces glutamic acid with lysine at codon 3397 of the RYR1 protein. Computational prediction is inconclusive regarding the impact of this variant on protein structure and function (internally defined REVEL score threshold 0.6 < inconclusive < 0.85, PMID: 27666373). To our knowledge, functional studies have not been reported for this variant. This variant has not been reported in individuals affected with RYR1-related disorders in the literature. This variant has been identified in 9/264640 chromosomes in the general population by the Genome Aggregation Database (gnomAD). The available evidence is insufficient to determine the role of this variant in disease conclusively. Therefore, this variant is classified as a Variant of Uncertain Significance. - |
RYR1-related disorder Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Invitae | Sep 19, 2022 | This sequence change replaces glutamic acid, which is acidic and polar, with lysine, which is basic and polar, at codon 3397 of the RYR1 protein (p.Glu3397Lys). This variant is present in population databases (rs201339536, gnomAD 0.03%). 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: 590362). 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) has been performed at Invitae for this missense variant, however the output from this modeling did not meet the statistical confidence thresholds required to predict the impact of this variant on 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 | PreventionGenetics, part of Exact Sciences | Jan 31, 2017 | - - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at