rs145183043

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

Scores

7
8
3

Clinical Significance

Uncertain significance criteria provided, multiple submitters, no conflicts U:7

Conservation

PhyloP100: 9.88
Variant links:
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]

Genome browser will be placed here

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
RYR1NM_000540.3 linkuse as main transcriptc.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
RYR1ENST00000359596.8 linkuse as main transcriptc.7844G>A p.Arg2615His missense_variant 49/1065 NM_000540.3 ENSP00000352608 A2P21817-1
RYR1ENST00000355481.8 linkuse as main transcriptc.7844G>A p.Arg2615His missense_variant 49/1051 ENSP00000347667 P4P21817-2
RYR1ENST00000594335.5 linkuse as main transcriptc.1298G>A p.Arg433His missense_variant, NMD_transcript_variant 10/491 ENSP00000470927
RYR1ENST00000599547.6 linkuse as main transcriptc.7844G>A p.Arg2615His missense_variant, NMD_transcript_variant 49/802 ENSP00000471601

Frequencies

GnomAD3 genomes
AF:
0.0000593
AC:
9
AN:
151846
Hom.:
0
Cov.:
29
show subpopulations
Gnomad AFR
AF:
0.0000969
Gnomad AMI
AF:
0.00
Gnomad AMR
AF:
0.00
Gnomad ASJ
AF:
0.00
Gnomad EAS
AF:
0.000194
Gnomad SAS
AF:
0.00
Gnomad FIN
AF:
0.00
Gnomad MID
AF:
0.00318
Gnomad NFE
AF:
0.0000147
Gnomad OTH
AF:
0.000958
GnomAD3 exomes
AF:
0.0000802
AC:
20
AN:
249272
Hom.:
0
AF XY:
0.0000371
AC XY:
5
AN XY:
134898
show subpopulations
Gnomad AFR exome
AF:
0.000308
Gnomad AMR exome
AF:
0.000145
Gnomad ASJ exome
AF:
0.00
Gnomad EAS exome
AF:
0.000163
Gnomad SAS exome
AF:
0.0000327
Gnomad FIN exome
AF:
0.00
Gnomad NFE exome
AF:
0.0000440
Gnomad OTH exome
AF:
0.000163
GnomAD4 exome
AF:
0.0000980
AC:
143
AN:
1458916
Hom.:
0
Cov.:
33
AF XY:
0.0000909
AC XY:
66
AN XY:
725838
show subpopulations
Gnomad4 AFR exome
AF:
0.000209
Gnomad4 AMR exome
AF:
0.000112
Gnomad4 ASJ exome
AF:
0.00
Gnomad4 EAS exome
AF:
0.000428
Gnomad4 SAS exome
AF:
0.000104
Gnomad4 FIN exome
AF:
0.00
Gnomad4 NFE exome
AF:
0.0000872
Gnomad4 OTH exome
AF:
0.000132
GnomAD4 genome
AF:
0.0000592
AC:
9
AN:
151962
Hom.:
0
Cov.:
29
AF XY:
0.0000673
AC XY:
5
AN XY:
74264
show subpopulations
Gnomad4 AFR
AF:
0.0000966
Gnomad4 AMR
AF:
0.00
Gnomad4 ASJ
AF:
0.00
Gnomad4 EAS
AF:
0.000195
Gnomad4 SAS
AF:
0.00
Gnomad4 FIN
AF:
0.00
Gnomad4 NFE
AF:
0.0000147
Gnomad4 OTH
AF:
0.000948
Alfa
AF:
0.0000625
Hom.:
0
Bravo
AF:
0.0000718
TwinsUK
AF:
0.000270
AC:
1
ALSPAC
AF:
0.00
AC:
0
ESP6500AA
AF:
0.000227
AC:
1
ESP6500EA
AF:
0.000116
AC:
1
ExAC
AF:
0.0000824
AC:
10
EpiCase
AF:
0.00
EpiControl
AF:
0.0000593

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 submitterclinical testingRevvity Omics, RevvityMar 16, 2023- -
Uncertain significance, no assertion criteria providedclinical testingDepartment 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 submitterclinical testingGeneDxJul 11, 2023Observed 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 submitterclinical testingLabcorp Genetics (formerly Invitae), LabcorpSep 22, 2022This 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 providedclinical testingPreventionGenetics, part of Exact SciencesJul 25, 2024The 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 submitterclinical testingAll of Us Research Program, National Institutes of HealthDec 13, 2023This 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 submitterclinical testingFulgent Genetics, Fulgent GeneticsSep 01, 2021- -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Uncertain
0.43
BayesDel_addAF
Uncertain
0.12
D
BayesDel_noAF
Pathogenic
0.24
CADD
Pathogenic
30
DANN
Uncertain
1.0
DEOGEN2
Uncertain
0.79
.;D
Eigen
Uncertain
0.68
Eigen_PC
Uncertain
0.63
FATHMM_MKL
Pathogenic
0.98
D
LIST_S2
Uncertain
0.95
D;D
M_CAP
Pathogenic
0.75
D
MetaRNN
Pathogenic
0.81
D;D
MetaSVM
Pathogenic
1.0
D
MutationAssessor
Benign
1.6
L;L
MutationTaster
Benign
1.0
D;D;D
PrimateAI
Pathogenic
0.81
D
PROVEAN
Uncertain
-4.0
D;D
REVEL
Pathogenic
0.81
Sift
Benign
0.099
T;T
Polyphen
1.0
D;D
Vest4
0.86
MVP
1.0
MPC
0.55
ClinPred
0.28
T
GERP RS
4.1
Varity_R
0.23
gMVP
0.62

Splicing

Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
0.0
Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Below is the list of publications found by LitVar. It may be empty.

Other links and lift over

dbSNP: rs145183043; hg19: chr19-38993528; API