chr19-38459298-G-A
Variant summary
Our verdict is Uncertain significance. Variant got 4 ACMG points: 4P and 0B. PM1PP2PP3
The NM_000540.3(RYR1):c.2320G>A(p.Gly774Arg) variant causes a missense change. The variant allele was found at a frequency of 0.000234 in 1,614,058 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. G774W) 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 4 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
RYR1 | NM_000540.3 | c.2320G>A | p.Gly774Arg | missense_variant | 19/106 | ENST00000359596.8 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
RYR1 | ENST00000359596.8 | c.2320G>A | p.Gly774Arg | missense_variant | 19/106 | 5 | NM_000540.3 | A2 | |
RYR1 | ENST00000355481.8 | c.2320G>A | p.Gly774Arg | missense_variant | 19/105 | 1 | P4 | ||
RYR1 | ENST00000599547.6 | c.2320G>A | p.Gly774Arg | missense_variant, NMD_transcript_variant | 19/80 | 2 |
Frequencies
GnomAD3 genomes AF: 0.000184 AC: 28AN: 152060Hom.: 0 Cov.: 31
GnomAD3 exomes AF: 0.000267 AC: 67AN: 251402Hom.: 0 AF XY: 0.000302 AC XY: 41AN XY: 135878
GnomAD4 exome AF: 0.000239 AC: 350AN: 1461880Hom.: 0 Cov.: 35 AF XY: 0.000235 AC XY: 171AN XY: 727244
GnomAD4 genome AF: 0.000184 AC: 28AN: 152178Hom.: 0 Cov.: 31 AF XY: 0.000175 AC XY: 13AN XY: 74390
ClinVar
Submissions by phenotype
not provided Uncertain:6
Uncertain significance, criteria provided, single submitter | clinical testing | GeneDx | Aug 10, 2020 | Identified in a fetus with multiple congenital anomalies; however, a second RYR1 variant was not detected and information regarding parental testing was not available (Becher et al., 2020); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function This variant is associated with the following publications: (PMID: 32304219, 30325262) - |
Uncertain significance, no assertion criteria provided | clinical testing | Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC) | - | - - |
Uncertain significance, no assertion criteria provided | clinical testing | Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center | - | - - |
Uncertain significance, criteria provided, single submitter | clinical testing | Revvity Omics, Revvity | May 25, 2023 | - - |
Uncertain significance, criteria provided, single submitter | clinical testing | PreventionGenetics, part of Exact Sciences | Mar 22, 2016 | - - |
Uncertain significance, criteria provided, single submitter | clinical testing | CeGaT Center for Human Genetics Tuebingen | Nov 01, 2023 | RYR1: PP3 - |
RYR1-related disorder Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Invitae | Oct 01, 2022 | This sequence change replaces glycine, which is neutral and non-polar, with arginine, which is basic and polar, at codon 774 of the RYR1 protein (p.Gly774Arg). This variant is present in population databases (rs147918857, gnomAD 0.05%). 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: 496666). 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. Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may create or strengthen a splice site. 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, susceptibility to, 1 Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | All of Us Research Program, National Institutes of Health | Feb 05, 2024 | This missense variant replaces glycine with arginine at codon 774 of the RYR1 protein. Computational prediction is inconclusive regarding the impact of this variant on protein structure and function (internally defined REVEL score threshold 0.5 < inconclusive < 0.7, 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 71/282750 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. - |
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. - |
RYR1-related myopathy Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Molecular Genetics, Royal Melbourne Hospital | Feb 05, 2024 | This sequence change in RYR1 is predicted to replace glycine with arginine at codon 774, p.(Gly774Arg). The glycine residue is highly conserved (100 vertebrates, UCSC), and is located in exon 19. There is a large physicochemical difference between glycine and arginine. The highest population minor allele frequency in gnomAD v4.0 is 0.03% (354/1,180,014 alleles) in the European (non-Finnish) population. This variant has been observed heterozygous in multiple individuals with inconsistent phenotypes or an alternative cause of disease was identified (PMID: 24627108, 27545679, 30325262, 32304219), and has been reported compound heterozygous (confirmed in trans) with a variant of uncertain significance in an individual with global developmental delay (DECIPHER). This variant has been observed in at least one individual with a negative in vitro contracture test (PMID: 32236737). Computational evidence is uninformative for the missense substitution (REVEL = 0.623). Based on the classification scheme RMH Modified ACMG Guidelines v1.6.1, this variant is classified as a VARIANT OF UNCERTAIN SIGNIFICANCE. Following criteria are met: PM2_Supporting. - |
Congenital myopathy with fiber type disproportion;C0751951:Central core myopathy;C1840365:King Denborough syndrome;C1850674:Congenital multicore myopathy with external ophthalmoplegia;C2930980:Malignant hyperthermia, susceptibility to, 1 Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Fulgent Genetics, Fulgent Genetics | Sep 01, 2021 | - - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at