rs145183043
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Variant summary
Our verdict is Uncertain significance. Variant got 2 ACMG points: 2P and 0B. PP2PP3
The NM_000540.3(RYR1):c.7844G>A(p.Arg2615His) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000944 in 1,610,878 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 (★★).
Frequency
Genomes: 𝑓 0.000059 ( 0 hom., cov: 29)
Exomes 𝑓: 0.000098 ( 0 hom. )
Consequence
RYR1
NM_000540.3 missense
NM_000540.3 missense
Scores
7
8
3
Clinical Significance
Conservation
PhyloP100: 9.88
Genes affected
RYR1 (HGNC:10483): (ryanodine receptor 1) This gene encodes a ryanodine receptor found in skeletal muscle. The encoded protein functions as a calcium release channel in the sarcoplasmic reticulum but also serves to connect the sarcoplasmic reticulum and transverse tubule. Mutations in this gene are associated with malignant hyperthermia susceptibility, central core disease, and minicore myopathy with external ophthalmoplegia. Alternatively spliced transcripts encoding different isoforms have been described. [provided by RefSeq, Jul 2008]
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ACMG classification
Classification made for transcript
Verdict is Uncertain_significance. Variant got 2 ACMG points.
PP2
Missense variant in gene, where missense usually causes diseases (based on misZ statistic), RYR1. . Gene score misZ 1.918 (greater than the threshold 3.09). Trascript score misZ 3.9788 (greater than threshold 3.09). GenCC has associacion of gene with King-Denborough syndrome, congenital multicore myopathy with external ophthalmoplegia, autosomal recessive centronuclear myopathy, RYR1-related myopathy, lethal multiple pterygium syndrome, malignant hyperthermia of anesthesia, benign Samaritan congenital myopathy, malignant hyperthermia, susceptibility to, 1, congenital myopathy with myasthenic-like onset, central core myopathy.
PP3
MetaRNN computational evidence supports a deleterious effect, 0.807
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | Protein | UniProt |
---|---|---|---|---|---|---|---|---|
RYR1 | NM_000540.3 | c.7844G>A | p.Arg2615His | missense_variant | 49/106 | ENST00000359596.8 | NP_000531.2 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Protein | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|---|
RYR1 | ENST00000359596.8 | c.7844G>A | p.Arg2615His | missense_variant | 49/106 | 5 | NM_000540.3 | ENSP00000352608 | A2 | |
RYR1 | ENST00000355481.8 | c.7844G>A | p.Arg2615His | missense_variant | 49/105 | 1 | ENSP00000347667 | P4 | ||
RYR1 | ENST00000594335.5 | c.1298G>A | p.Arg433His | missense_variant, NMD_transcript_variant | 10/49 | 1 | ENSP00000470927 | |||
RYR1 | ENST00000599547.6 | c.7844G>A | p.Arg2615His | missense_variant, NMD_transcript_variant | 49/80 | 2 | ENSP00000471601 |
Frequencies
GnomAD3 genomes AF: 0.0000593 AC: 9AN: 151846Hom.: 0 Cov.: 29
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GnomAD3 exomes AF: 0.0000802 AC: 20AN: 249272Hom.: 0 AF XY: 0.0000371 AC XY: 5AN XY: 134898
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GnomAD4 exome AF: 0.0000980 AC: 143AN: 1458916Hom.: 0 Cov.: 33 AF XY: 0.0000909 AC XY: 66AN XY: 725838
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GnomAD4 genome AF: 0.0000592 AC: 9AN: 151962Hom.: 0 Cov.: 29 AF XY: 0.0000673 AC XY: 5AN XY: 74264
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ClinVar
Significance: Uncertain significance
Submissions summary: Uncertain:7
Revision: criteria provided, multiple submitters, no conflicts
LINK: link
Submissions by phenotype
not provided Uncertain:3
Uncertain significance, criteria provided, single submitter | clinical testing | Revvity Omics, Revvity | Mar 16, 2023 | - - |
Uncertain significance, no assertion criteria provided | clinical testing | Department of Pathology and Laboratory Medicine, Sinai Health System | - | The RYR1 p.Arg2615His variant was not identified in the literature but was identified in dbSNP (ID: rs145183043) and ClinVar (classified as uncertain significance by Invitae and Prevention Genetics). The variant was identified in control databases in 21 of 280550 chromosomes at a frequency of 0.00007485 (Genome Aggregation Database March 6, 2019, v2.1.1). The variant was observed in the following populations: African in 6 of 24906 chromosomes (freq: 0.000241), East Asian in 3 of 19924 chromosomes (freq: 0.000151), Latino in 5 of 35422 chromosomes (freq: 0.000141), Other in 1 of 7210 chromosomes (freq: 0.000139), European (non-Finnish) in 5 of 128914 chromosomes (freq: 0.000039) and South Asian in 1 of 30610 chromosomes (freq: 0.000033), but was not observed in the Ashkenazi Jewish or European (Finnish) populations. The p.Arg2615 residue is not conserved in mammals and computational analyses (PolyPhen-2, SIFT, AlignGVGD, BLOSUM, MutationTaster) provide inconsistent predictions regarding the impact to the protein; this information is not very predictive of pathogenicity. The variant occurs outside of the splicing consensus sequence and in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer) do not predict a difference in splicing. In summary, based on the above information the clinical significance of this variant cannot be determined with certainty at this time. This variant is classified as a variant of uncertain significance. - |
Uncertain significance, criteria provided, single submitter | clinical testing | GeneDx | Jul 11, 2023 | Observed in patient with congenital axial hypotonia and normal serum CK in published literature (Gonzalez-Quereda et al., 2020); however, no further clinical information was provided.; 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: 32403337) - |
RYR1-related disorder Uncertain:2
Uncertain significance, criteria provided, single submitter | clinical testing | Labcorp Genetics (formerly Invitae), Labcorp | Sep 22, 2022 | This sequence change replaces arginine, which is basic and polar, with histidine, which is basic and polar, at codon 2615 of the RYR1 protein (p.Arg2615His). The frequency data for this variant in the population databases is considered unreliable, as metrics indicate poor data quality at this position in the gnomAD database. This missense change has been observed in individual(s) with clinical features of congenital myopathy (PMID: 32403337). ClinVar contains an entry for this variant (Variation ID: 478280). 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. - |
Uncertain significance, no assertion criteria provided | clinical testing | PreventionGenetics, part of Exact Sciences | Jul 25, 2024 | The RYR1 c.7844G>A variant is predicted to result in the amino acid substitution p.Arg2615His. This variant was reported in the heterozygous state in an individual with congenital myopathy; however, pathogenicity was not established (Gonzalez-Quereda et al 2020. PubMed ID: 32403337). This variant is reported in 0.024% of alleles in individuals of African descent in gnomAD. A different missense change affecting this residue has been reported in patients with myopathy without further evidence of pathogenicity (c.7843C>T, p.Arg2615Cys; Rocha et al. 2014. PubMed ID: 24950660, Invernizzi et al. 2023. PubMed ID: 37510298; Sanga et al. 2021. PubMed ID: 33124102). At this time, the clinical significance of the c.7844G>A variant is uncertain due to the absence of conclusive functional and genetic evidence. - |
Malignant hyperthermia, susceptibility to, 1 Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | All of Us Research Program, National Institutes of Health | Dec 13, 2023 | This missense variant replaces arginine with histidine at codon 2615 of the RYR1 protein. Computational prediction suggests that this variant may have deleterious impact on protein structure and function (internally defined REVEL score threshold >= 0.7, PMID: 27666373). To our knowledge, functional studies have not been reported for this variant. This variant has been reported in an individual affected with congenital myopathy (PMID: 32403337). This variant has not been identified 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. - |
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:
Name
Calibrated prediction
Score
Prediction
AlphaMissense
Uncertain
BayesDel_addAF
Uncertain
D
BayesDel_noAF
Pathogenic
CADD
Pathogenic
DANN
Uncertain
DEOGEN2
Uncertain
.;D
Eigen
Uncertain
Eigen_PC
Uncertain
FATHMM_MKL
Pathogenic
D
LIST_S2
Uncertain
D;D
M_CAP
Pathogenic
D
MetaRNN
Pathogenic
D;D
MetaSVM
Pathogenic
D
MutationAssessor
Benign
L;L
MutationTaster
Benign
D;D;D
PrimateAI
Pathogenic
D
PROVEAN
Uncertain
D;D
REVEL
Pathogenic
Sift
Benign
T;T
Polyphen
D;D
Vest4
MVP
MPC
0.55
ClinPred
T
GERP RS
Varity_R
gMVP
Splicing
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SpliceAI score (max)
Details are displayed if max score is > 0.2
Find out detailed SpliceAI scores and Pangolin per-transcript scores at